Update History for: EcoCyc | MetaCyc | BsubCyc | HumanCyc |YeastCyc

BioCyc Update History

This document summarizes the history of updates to BioCyc.

 

The statistics for each year pertain to the last BioCyc release in that year.

Release Notes for BioCyc Version 29.6

Released on February 26, 2025.

Version 29.6 is a minor release that includes updates to the BioCyc website and downloadable data files.

Version 29.6 of BioCyc contains 20,086 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

Updates to Tier 2 Acinetobacter baumannii ATCC 17978 Database

We have significantly updated aspects related to lipid biosynthesis and transport proteins that affect the resistance or susceptibility of A. baumannii to antibiotics:

• New reactions that occur under cold conditions (e.g. 15 °C) were added to the (Kdo)₃ lipid A biosynthesis pathway, based on work from Herrera et al. 2021.
• Reactions that occur under typical experimental temperatures (e.g. 37 °C) were clarified, such as those carried out by core oligosaccharide glycosyltransferase GtrOC1 (A1S-2903) and core oligosaccharide glycosyltransferase LpsB, as shown by VanOtterloo et al. 2024 and Luke et al. 2010.
• Summaries of several enzymes involved in the (Kdo)₃ lipid A biosynthesis pathway, octanoyl acyltransferase LpxS, lipid A hydroxylase LpxO and (Kdo)2-lipid IVA lauroyltransferase LpxM, were also updated.
• Overexpression experiments with multidrug efflux pumps, such as AdeFGH were updated to reflect how high levels of fluoroquinolones, such as ciprofloxacin, affect the cell's ability to resist antibiotics (Hamami et al. 2025).
• Lpt genes involved in the lipopolysaccharide transport system and lpx genes involved in (Kdo)₃ lipid A biosynthesis pathway were found to be essential for surviving antibiotics in a CRISPR interference knockdown study by Tran et al. 2025.
• A new, A. baumannii-specific RNA polymerase sigma factor SigAb was found that responds to metal stress, such as high copper levels relevant to hospital settings, and regulates a few genes directly, including itself, and a variety of other genes indirectly. Two anti-SigAb proteins coded by genes within the same operon as SigAb, AabA and AabB, were also identified and found to be important to cell fitness (Bacon et al. 2025).

Updates to Tier 2 Vibrio cholerae O1 El Tor N16961

The PGDB representing the reference genome of the pathogen Vibrio cholerae strain O1 El Tor N16961 received significant upgrades, with extensive coverage of genomic systems contributing to pathogenicity. This release includes several upgrades reflecting recent and/or significant findings for this pathogen, including the characterization of:

• The dual roles of the incomplete nitrate reduction pathway of V. cholerae
• Genomic systems contributing to biofilm dispersal (Vibrio exopolysaccharide degradation by the α-1,4-polysaccharide lyase RbmB, matrix protein degradation by the calcium-dependent periplasmic protease LapG of the LapDG/c-di-GMP signaling module, and the novel two-component system encoded by the dbfQRS operon)
• Transport systems (the chitobiose-specific phosphotransferase system and the L-glutamate/L-glutamine TAXI-TRAP transporter GluPQM)
• Novel antimicrobial resistance mechanisms and functions (the contributions of the carR-carS-ompV-virK operon and the VexAB-TolC effux pump to polymyxin B resistance)
• Virulence regulation (identification of the novel VexAB regulator atrR and the role of the chitobiose-specific phosphotransferase system repressor ChsR in positive regulation of the virulence activator TcpP)
• Anti-phage (AvcID) and plasmid destabilization systems (DdmABC and DdmDE)

Updates to MetaCyc Version 29.6

New and Updated Pathways

We have added 17 new pathways to MetaCyc since the 29.5 release and revised 7 existing pathways, for a total of 24 new and revised pathways _{[more info]}.

Other Improvements

Update of EC Reactions

During this quarter we have updated the Enzyme Commission (EC) definitions in MetaCyc with the latest information (as of February 2026) from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) and the Joint Commission on Biochemical Nomenclature (JCBN), available from the ExplorEnz database. MetaCyc now contains 6930 EC numbers (including internal M numbers).

Updates to EcoCyc Version 29.6

• AdiY: Added the AdiY tetramer entity and curated links to acid-inducible genes/units (including adiA and adiC). Updated the AdiY summary to describe it as a cytoplasmic pH sensor with state-/conformation-dependent regulatory behavior. (Gallo et al. 2026).
• RpoH (σ32): Updated the RpoH summary with evidence that σ32 binds the second messenger c-di-GMP, consistent with conserved receptor-like behavior; inhibitory effects on DNA binding have also been reported in another proteobacterium. (Huo et al. 2025).
• ToiL: Added the ToiL uORF-encoded peptide and updated TU notes for the toiL-topAI-yjhQ operon, consistent with a translation-stress-responsive regulatory mechanism (Baniulyte and Wade 2025).

Release Notes for BioCyc Version 29.5

Released on Dec 15, 2025.

Version 29.5 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 29.5 of BioCyc contains 20,086 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

New Curated Tier 2 Database for Neisseria meningitidis MC58

In healthy adults, Neisseria meningitidis commonly colonizes the nasopharynx asymptomatically. However, hyperinvasive clonal complexes can cause invasive meningococcal disease (IMD), a severe and potentially fatal infection of the bloodstream and/or cerebrospinal fluid. This release includes a manually curated PGDB for the reference genome of this species, N. meningitidis MC58. Examples of upgrades to this PGDB include:

• The curation of critical virulence factors and/or vaccine targets, including annotation of genes involved in capsule biosynthesis (see siaD and CtrABCD), genes of the pilin glycosylation pathway (see pglA), iron scavenging systems (lactoferrin binding receptor system,TonB-dependent transferrin iron outer membrane transport complex, and ferric iron ABC transporter), and surface-exposed proteins (factor H-binding protein FhbP, porA, nadA, opcA, and the Opa protein family).
• The annotation of phase-variable genes, including functional sequence reconstruction of frameshifted phase-variable loci, such as the pilC2, opaJ, the pilin glycosylation enzyme PglE, and the type III restriction-modification methyltransferase modA11, including the import of the putative regulon of ModA11 (275 genes).
• The annotation of various genomic islands, including:
  • IHT-A1, IHT-A2, IHT-B, IHT-C, and IHT-E
  • MuMenB/NeisMu1 and NeisMu2
  • MDA/Nf1-B1, MDA/Nf1-B2, Nf2-B1, and Nf2-B2

Updates to Tier 2 Lactiplantibacillus plantarum WCFS1 Database

L. plantarum is a nonpathogenic, facultative heterofermentive lactic acid bacterium capable of fermenting a large variety of sugar sources, though its predominant fermentation on hexose sugars is homolactic. L. plantarum occupies an exceptionally diverse range of habitats, including plants, fermented fruits and vegetables, meat and dairy products, and the gastrointestinal tract of organisms as varied as humans and Drosophila fruit flies.

This PGDB has undergone significant curation since its initial release at the Tier 2 level. During the curation process we removed dozens of previously predicted pathways, created 12 new pathways, modified 20 existing pathways, and imported 31 additional pathways from MetaCyc. Literature citations increased by more than 730 (from 1,421 to 2,154). We updated the annotated functions of over 250 proteins—60 of which are now assigned specific reactions—and created 80 new protein complexes. The total number of reactions increased by 176, including 50 transport reactions.

Experimental evidence codes are now assigned to 178 proteins, up from 53, and protein commentary has been substantially enriched: the number of entries containing more than 500 characters of commentary increased from 39 to 465.

Regulatory annotation also expanded markedly: regulatory interactions increased from 1 to 340, including 243 transcription factor binding sites and 11 riboswitches, and the number of genes with at least one known regulator rose from 0 to 490. Finally, we added detailed information on the four prophages embedded within the genome.

Examples for new pathways:

• NADH to nitrate electron transfer
• aryl-lactate biosynthesis
• pentose heterofermentation (via the phosphoketolase pathway)
• peptidoglycan biosynthesis (L. plantarum)
• poly(glycerol phosphate) wall teichoic acid biosynthesis
• poly(ribitol phosphate) wall teichoic acid biosynthesis I
• UDP-N-acetylmuramoyl-pentadepsipeptide biosynthesis (Lactobacillus plantarum)
• linoleate conversion to conjugated fatty acids

Examples for newly curated proteins:

• capsular polysaccharide 1 glycosyltransferase Cps1A
• peptidoglycan N-acetylglucosaminidase Acm2
• pyruvate oxidase PoxB
• putative Mn²⁺:H⁺ symporter MntH2
• extracellular electron transfer protein A
• plantaricin A-sensing response regulator PlnD
• a protein with a motif recognized by sortase A

Updates to MetaCyc Version 29.5

We have added 6 new pathways to MetaCyc since the 29.1 release and revised 6 existing pathways, for a total of 12 new and revised pathways _{[more info]}.

Updates to EcoCyc Version 29.5

Improvements to the EcoCyc Database

Using a systematic mass spectrometry (MS) quantitative screening and spectrophotometric assessment of enzyme-metabolite activity, Gruber et al. 2025 were able to identify and validate regulatory interactions between enzymes and allosteric effectors, many of which were found to play a role in regulation of core metabolic pathways, such as activators and inhibitors of maeA and maeB in gluconeogenesis and gnd in the pentose phosphate pathway.

Two proteins, GatZ and KbaZ, previously considered to be non-catalytic, were shown to be D-tagatose 6-P epimerases that carry out the conversion of keto-D-tagatose 6-phosphate → keto-D-fructose 6-phosphate. Additionally, HxpA was found to be the hexitol phosphatase A that dephosphorylates D-tagatose-6-P to D-tagatose, thus revealing that E. coli K-12 has a native D-tagatose production pathway that is enhanced when pfkA and zwf, are deleted, thus removing the competing pathways from D-glucose-6-P to the pentose phosphate pathway and from D-fructose-6-P to glycolysis, respectively (Palur et al. 2025).

The original evidence code "Transcription initiation mapping" was updated for 172 promoters to reflect the experimental evidence more specifically:

• 143 promoters, e.g. adiYp and alaEp, now have the evidence code “Primer extension assay for transcription start site determination”
• 29 promoters, e.g. dnaNp4 and glnLp, now have the evidence code “S1 nuclease protection assay evidence for transcription start site determination”.

Summaries for 165 transcription factors (TFs) were also expanded with new information. Examples include:

• A genome-wide CRISPRi, transcriptomic, and ChIP-seq analyses of E. coli under gentamicin exposure found that the DNA-binding transcriptional dual regulator CpxR is involved in the cellular response to gentamicin by directly repressing genes encoding respiratory complexes, leading to membrane depolarization and reduced gentamicin uptake. Additionally, the activity of another DNA-binding transcriptional dual regulator ArcA repressed under gentamicin exposure (Choe et al. 2025).
• Another transcriptional regulator, the repressor CytR, forms condensates in the presence of inorganic polyphosphate (polyP), a ubiquitous molecule produced under stress conditions, suggesting that polyP may sequester CytR and prevent it from performing its role (Goyal et al. 2025).
• Singh et al. (2025) identified 4 amino acid residues that play distinct roles in the allosteric regulation and DNA-binding activity of the DNA-binding transcriptional repressor DgoR.
• The transcriptional regulator LeuO was found to interact with the metabolite (2S)-2-isopropylmalate, forming a new active conformation, LeuO-(2S)-2-isopropylmalate complex (Trouillon et al. 2025).

2. Improvements to the BioCyc Website

Improvements to the BioCyc website tools include the following.

• Molecular Diagrams: Protein complex pages can now contain diagrams depicting the major components of large protein complexes and their interactions. The diagrams can be overlayed with omics data to speed understanding of subunit abundance patterns. A dozen such diagrams are now available for EcoCyc, such as the primosome and nitrate reductase A.

• Introns and Exons: The Genome Explorer genome browser now depicts introns and exons for eukaryotic genomes [example].

• 3D Structure Tab: Protein and compound pages can now include a "Structure" tab that presents a rotateable diagram of the protein or compound 3D structure [example]. Protein 3D structures are sourced from PDB, AlphaFold and QSProteome. Compound 3D structures are sourced from PubChem.

• Isoforms Tab: Protein pages can now include an "Isoforms" tab that lists the known isoforms of the protein and depicts their introns and exons [example].

• Protein Features Tab: The "Protein Features" tab within protein pages has been upgraded to provide a tooltip for each depicted feature, and so that mousing over a feature in the feature table highlights the feature in the sequence portion of the diagram (and vice-versa) [example].

• Omics Data Analysis
  • Omics Data on Metabolic Network Explorer: It is now possible to overlay omics data on the Metabolic Network Explorer tool.

  • Omics Pop-Ups: Omics pop-up charts are now more compact, enabling display of more time points. A new algorithm produces improved layouts of multiple omics pop-ups on a pathway page. When a user navigates to a new pathway page, omics pop-ups for that pathway are now shown automatically.

Release Notes for BioCyc Version 29.1

Released on September 22, 2025.

Version 29.1 is a minor release that includes updates to the BioCyc website and downloadable data files.

Version 29.1 of BioCyc contains 20,079 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

Release Notes for HumanCyc Version 29.1

With version 29.5 we introduced major revisions to the HumanCyc database. Previously, HumanCyc included only the genomic coordinates of genes but not the full sequence. Beginning with this release, the database now incorporates the complete human genome sequence.

Since the creation of HumanCyc, the quality of human genome annotation has advanced considerably, resulting in a larger set of identified genes, shifts in their genomic positions, and refined functional annotations. To reflect these improvements, we updated HumanCyc to the most recent NCBI annotation as of September 30, 2024. This update expanded the gene count from 21,083 (including 4,826 unmapped genes) to 59,059 (with only a single unmapped gene). The vast majority of the new genes are RNA genes and pseudogenes; the number of protein-encoding genes actually decreased rom 20,737 to 20,487.

A substantial effort went into reconciling differences between older and newer annotations, remapping genes to updated positions, and revising their functional descriptions as needed. Isoforms were also introduced into HumanCyc, increasing the number of polypeptides from 20,765 to 93,431. Following UniProt’s convention, one isoform per protein was designated as the canonical form. A new "Isoforms tab" was added to the protein pages, listing the isoforms.

Beyond sequence and annotation updates, HumanCyc content was further enriched. The number of base pathways increased to 395, and the number of enzymatic reactions rose from 2,958 to 3,172. For the first time, protein features were incorporated from UniProt, adding 428,277 new annotations.

New Curated Tier 2 Database for Vibrio natriegens ATCC 14048

Vibrio natriegens is a non-pathogenic Gram-negative halophilic marine bacterium of the Vibrionaceae family. It is found in nutrient rich coastal and estuarine environments, and holds the record for the shortest known doubling time of any free-living microbe (under 10 minutes in optimal conditions). This exceptional growth rate, combined with its metabolic versatility and natural competence, have made V. natriegens a promising chassis organism in synthetic biology. This release includes a manually curated PGDB for the reference genome of V. natriegens ATCC 14048. This PGDB has benefited from ortholog propagation from the manually curated PGDB for Vibrio cholerae O1 El Tor N16961. It has also received upgrades on central metabolic enzymes (for example, Na+-translocating NADH:ubiquinone oxidoreductase, periplasmic nitrate reductase and nitrite reductase); and pathways (for example glycolysis III (from glucose), TCA cycle I (prokaryotic), NADH to cytochrome bo oxidase electron transfer II,superpathway of acetate utilization and formation). In addition, large-scale datasets were imported into the curated PGDB, including co-expression data from iModulonDB, and gene essentiality data from Lee et al..

Updates to MetaCyc Version 29.1

We have added 41 new pathways to MetaCyc since the 29.0 release and revised 15 existing pathways, for a total of 56 new and revised pathways._{[more info]}

Updates to EcoCyc Version 29.1

Improvements to the EcoCyc Database

• Seven uncharacterized or partially characterized "y-genes" (ybiJ, ycfJ, ycgZ, ydgU, yhcN, yhdV and yjcB) were found to increase translation when exposed to low pH (pH 4.4) as measured by mRNA levels by RT-qPCR Schumacher et al. (2023).
• A previously uncharacterized gene (yhiN) was characterized by Toubdji et al. (2024) as a ribosomal dihydrouridine synthase and renamed rdsA. Using a new method that blocks reverse transcriptase by labelling dihydrouridine with rhodoamine (called RhoRT-PCR), RdsA was found to carry out dihydrouridylation of uracil²⁴⁴⁹ in the 23S rRNA positioned at the peptidyl transferase site of the ribosome. A new reaction for 23S rRNA dihydrouridylation has been added.
• We have also significantly updated the summaries of three tRNA dihydrouridine synthases, DusA, DusB, and DusC, with respect to their relative roles in tRNA dihydrouridylation.
• We imported datasets of lysine lactylation sites in E. coli proteins (Dong et al. 2022) carried out by YiaC, which can lactylate lysine residues as well as acetylate lysine residues, though not always the same ones. We also found that EcoCyc was missing the lysine succinylation and associated acetylation sites from (Weinert et al. 2013) – thanks to the user who pointed this out to us! These lysine succinylation sites have also been imported. Posttranslational modifications of amino acids can be found by clicking on the Protein Features tab on protein information pages in EcoCyc.
• We have also curated aspects of a large protein-protein interaction (PPI) study by Chowdhury et al. (2024) that identified interactions related to glycolysis. Several partially and uncharacterized genes were found to be involved in glycolytic enzyme interactions, such as YdiL interacting with both Eno and GapA, YjhP interacting with GpmI, and YodC interacting with PykA. Three protein-enzyme interactions (PEIs) (RpsB-AdhE, DcyD-NanE and MinE-Yccx), previously not known to regulate metabolism, were identified. A follow-up study of PEIs, defined as the connection between PPI and metabolomic networks, found three previously unknown PEI pairs are likely involved in regulation of carbohydrate metabolism (Chowdhury et al. 2025).
• Ten CRISPR repeat regions were entered for MG1655 based on Brouns et al. 2008; these can be visualized within the Genome Browser as Extragenic Sites (see Legend panel popup) between genes iap and cas2
• A minor project to audit and update our representation of iron-sulfur (Fe-S) cofactors was completed and a further 22 proteins are now correctly represented as Fe-S cluster binding, based on the experimental literature.
• Data from Abdullah et al. (2025) reporting the experimental determination of cellular copy number for ABC transporter proteins has been added to the database.
• New transport reactions have been added to the database for the import of copper mediated by the CopD-family protein copper transporter YebZ (Palmer et al. (2025)) and for the import of glutathione disulfide mediated by the ABC-family transporter complex GsiABCD (Knoke et al. 2025).
• We incorporated evidence and references from RNA-seq and ChIP-exo experiments reported in Jang et al. (2024), supporting the association between 56 promoters and the sigma factor RpoS that activates them.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 29.0

Released on April 10, 2025.

Version 29.0 is a major release that includes updates to the BioCyc website and downloadable data files.

Version 29.0 of BioCyc contains 20,077 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

Updates to Cupriavidus necator H16

Cupriavidus necator is a Gram-negative bacterium known for its remarkable ability to fix carbon dioxide and accumulate polyhydroxyalkanoates (PHAs). This versatile microorganism thrives in diverse environments and can grow by adopting both lithoautotrophic and heterotrophic lifestyles. Its metabolic flexibility and genetic tractability make it a valuable model organism for biotechnology and sustainable bioproduction research.

The current release includes a manually curated PGDB for Cupriavidus necator H16. This database has undergone significant manual curation, focusing on key aspects of the organism's biology, such as polyhydroxybutanoate (PHB) biosynthesis (PWY1-3), carbon dioxide fixation via the Calvin-Benson-Bassham cycle (CALVIN-PWY), NAD-dependent hydrogen oxidation (PWY-5382), and denitrification (PWY-6748). Transport systems, as well as key central metabolic and respiratory pathways, have also been manually curated.

New Curated Tier 2 Database for Nostoc/Anabaena sp. PCC 7120

Curation of the freshwater, filamentous, heterocyst-forming, Nostoc/Anabaena sp. PCC 7120 genome database was requested by the cyanobacteria research community at the 12^th European Workshop on the Biology of Cyanobacteria held in Sevilla, Spain, in Sept 2024. After initial curation by SRI's Ron Caspi, a group of researchers led by Jeff Elhai provided additional information for 72 proteins, 5 metabolic pathways, and 28 small regulatory RNAs, resulting in curated information from more than 444 peer-reviewed publications. In addition to the curation, information of orthologs from Synechocystis sp. PCC 6803 substr. Kazusa, another community curated cyanobacterium, was propagated to provide more information to the Nostoc/Anabaena sp. PCC 7120 genome database. Some notable examples of the curation include :

• Pathways related to cell envelopes of the heterocysts, such as Nostoc heterocyst envelope polysaccharide biosynthesis and heterocyst glycolipid biosynthesis, and genes that carry out these reactions, such as the HgdD-DevBCA transporter, which exports the complete heterocyst glycolipids across the inner membrane and cell wall to just outside the outer membrane and beneath the polysaccharide layer.
• The biosynthetic pathway for the cyanobacterial sunscreen, scytonemin.
• Proteins involved in determining the site of cell division, the MinCD complex, heterocyst differentiation, HetZ and inhibition of heterocyst formation, PatU3.
• A tandem array of twelve nitrogen stress-induced small regulatory RNAs starting with NsiR1.1 that compose a NsiR cluster upstream of and antisense to the cell division protease HetR.

Updates to MetaCyc Version 29.0

We have added 16 new pathways to MetaCyc since the 28.5 release and revised 6 existing pathways, for a total of 22 new and revised pathways._{[more info]}

Updates to EcoCyc Version 29.0

EcoCyc Curation Highlights

New functions have been determined for several genes, including five y-genes with previously unknown or putative functions:

• The structure and function of the EF-P paralog YeiP, now called EfpL, has been characterized and found to be involved in translational stress response through rescuing ribosome stalling at polyproline (XP(P)X)-containing proteins as well as acting as a sensor for the metabolic state of the cell via lysine acylation (Sieber et al).
• YoaC, YfeS, YlaC), were curated for their resistance to boric acid exposure based on mutational and complementation assays (Çöl et al).
• YgaV’s regulatory interactions and role in iron uptake in response to intracellular H₂S have been determined, confirming its role as a transcription factor. As a result, its name has been changed from 'putative DNA-binding transcriptional regulator YgaV' to 'DNA-binding transcriptional regulator YgaV' (Nonoyama et al).
• New oxidative and high heat stress-related tRNA^Tyr methylation capability has been determined for RsmF, which previously was only known to carry out m⁵C modification of the 16S ribosomal RNA (Valesyan et al).
• Using single-cell RNA-seq analysis Yan et al discovered that PdeI functions as a cyclic di-GMP synthase rather than a phosphodiesterase.
• Rex et al was able to rescue the ΔplsX ΔplsY synthetic lethality phenotype and determine that together these two proteins play a role in the fine-tuned regulation of lipid production and homeostasis of the cell envelope.

Three new reactions have been added to the important DNA repair enzyme, UvrABC excision nuclease, significantly improving the representation of its activity.

Regulation-related curation:

• In addition to our ongoing curation of transcriptional regulation and regulation of small RNAs, we added five regulatory interactions involving the protein CsrA, which regulates the translation of a variety of genes, including many related to carbohydrate metabolism (Gorelik et al).
• We also added further details to the RNA regulatory factors that control expression of the TonB-dependent BtuB membrane transporter responsible for the import of corrinoids such as vitamin B₁₂. Bastet et al have furthered our understanding of the regulation of btuB translation by two small RNAs and a riboswitch. A SmartTable listing all 11 riboswitches currently represented in EcoCyc can be easily accessed on the website under the Tools → SmartTables → Special SmartTables menu.
• Additionally, a new mechanism of regulation between the transcription factors (TFs) ZntR and Zur has been described in their corresponding summaries. It is noted that non-metallated ZntR (ZntR_apo) enhances the dissociation of Zur from DNA (Chakraborty et al).
• We have added information about a new conformation for the TF H-NS that occurs when the metabolite 2-C-methyl-D-erythritol-2,4-cyclodiphosphate (MEcPP) binds to H-NS when it is not bound to DNA, thus preventing the binding and repression of the fimE promoter by this TF (Guo et al). This is the first histone-like TF in EcoCyc for which the binding of a metabolite has been reported.
• We have also curated the regulatory interactions of the transcription factor Nac, based on RNA-seq and ChIP-exo experiments reported in Park et al.

2. Improvements to the BioCyc Website

Improvements to the BioCyc website tools include the following.

• Upgrades to Organism Summary Pages: We upgraded organism summary pages to present information in a modernized format (example).

• Upgrades to Transcription Unit Pages: We upgraded transcription unit pages to present regulatory information in a modernized format including new tabs within the pages (example).

• Omics Data Analysis
  • New Option for Display of Omics Data on Pathway Pages: When overlaying multi-column omics data on pathway pages, users now have the choice to view the data either as popups or, a new option, as colored icons embedded within the diagram.

  • New Omics Masterfile: During analysis of multi-omics datasets, a new option will generate an "omics masterfile" that links to several individual omics datasets and enables them all to be input in one operation.

Release Notes for BioCyc Version 28.5

Released on December 11, 2024.

Version 28.5 is a major release that includes updates to the BioCyc website and downloadable data files.

Version 28.5 of BioCyc contains 20,070 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

New Curated Tier 2 Database for Neisseria gonorrhoeae FA 1090

The betaproteobacterium Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection (STI) gonorrhoea. This pathogen has garnered increasing attention in the microbial research community due to its rapid rise in antimicrobial resistance, high transmissibility, and its ability to cause frequent asymptomatic infections. Although typically non-fatal, untreated gonorrhoea can result in serious secondary complications, including infertility in both men and women. In 2024, the World Health Organization included multidrug-resistant strains of N. gonorrhoeae (i.e., those resistant to third-generation cephalosporins and/or fluoroquinolones) as a high priority in its Bacterial Priority Pathogens List, emphasizing an urgent need for novel treatment strategies.

This release includes a manually curated PGDB for the gonococcal reference genome N. gonorrhoeae FA 1090. This database has undergone significant manual curation targeted at basic and notable biology of the organism, including central metabolism and respiration (see pathways TCA cycle and aerobic respiration I (cytochrome c)), transporters (see for example the TonB-dependent systems of iron and zinc acquisition), lipid A and lipooligosaccharide (LOS) biosynthesis, and antibiotic resistance. Critical virulence factors such as the Opa family of outer membrane proteins, 'Slam' proteins that are required for the display of surface lipoproteins, and the type IV pilus (including the pilS loci which facilitate phase variation of the major pilin expression locus) have also been correctly identified and annotated. Where possible, other putative or experimentally validated phase-variable genes in this organism have also been identified. In addition, a small collection of experimentally validated small RNAs and over 300 putative small RNAs identified via RNA-Seq have been imported into this database from McClure et. al. (2014) and Remmele et. al. (2014).

Updates to MetaCyc Version 28.5

We have added 25 new pathways to MetaCyc since the 28.1 release and revised 7 existing pathways, for a total of 32 new and revised pathways._{[more info]}

Updates to EcoCyc Version 28.5

We have added a dataset on E. coli protein turnover rates from Gupta et al (2024) to EcoCyc. Data are present on gene pages in the Summary tab under the heading Gene Product Active Half Life.

We have added links from EcoCyc gene pages to FoldSeek, which performs structure-similarity searches against the AlphaFold structural database and can find distant homology relationships that may provide clues regarding the function of a protein. From gene pages, see the right-sidebar Operations menu, and click on "Search the sequence in FoldSeek". Once the FoldSeek page appears, click Search on the bottom left.

We are now providing in the Unification Links panel on gene information pages links to the SHIGEN National BioResource Project for genes that have knockout mutant strains in the KEIO and/or ASKA collections.

EcoCyc Curation Highlights

The riboswitch-controlled transporter Alx has been characterized by Sharma et al. (2024) as a "low-activity" manganese ion exporter with a role in Mn²⁺ homeostasis at alkaline pH.

The function of an uncharacterized gene, ycgM, was determined to be a metabolite repair enzyme with oxaloacetate (OAA) tautomerase activity that removes the enol-OAA inhibition of succinate:quinone oxidoreductase (SDH) within the TCA cycle I (Zmuda et al. 2024).

We have modified and created new E. coli tRNA processing pathways, such as the polycistronic tRNA processing III and IV pathways, and superpathways of both polycistronic and monocistronic tRNA processes.

Bacterial AsmA-like proteins are structurally similar to a recently described family of eukaryotic bridge-like lipid transfer proteins. E. coli K-12 contains 6 AsmA-like paralogs including: the membrane-anchored protein YdbH now annotated as a putative intermembrane phospholipid transport protein based on a recent report by Kumar et al. (2024) providing evidence that YdbH and lipoprotein YnbE interact to form a bridge connecting the inner and outer membrane of the cell.

The kdpD-encoded histidine kinase has been reannotated as a serine histidine kinase. KdpD's atypical serine kinase activity mediates post-translational inhibition of the high-affinity K⁺-transporting P-type ATPase via phosphorylation of the KdpB subunit.

Regulatory interactions (RIs) of DNA-binding transcriptional dual regulator NtrC were annotated based on RNA-seq and ChIP-exo experiments reported in Park et al. (2023).

2. Improvements to the BioCyc Website

Improvements to the BioCyc website tools include the following.

• Nucleotide BLAST Searches: Users can now perform BLAST nucleotide searches against lists of organisms defined in SmartTables; previously only amino-acid multi-organism searches were supported.

• Enhancements to SmartTables
  • SmartTable Row Filtering: The user can now display only those rows in a SmartTable that contain a given search string, specified in the "Search" box in the upper right. Other SmartTable enhancements include the ability to customize the number of rows shown per page, and the ability to add multiple columns to a SmartTable as part of a single operation. Note that SmartTables no longer distinguish property columns from transformation columns.

  • New Visualization of SmartTable Enrichment Results: After generating a SmartTable enrichment analysis based on pathways or GO terms, there is a new option to map the resulting SmartTable onto an ontology viewer, to see how the most highly enriched terms are related to each other. Select Paint Data → on Ontology Viewer from the Operations menu. [Learn more about SmartTable Enrichment Analysis]

  • SmartTable for Pathway Holes: A new special SmartTable has been added that enumerates all pathway holes in the current organism (all reactions for which no gene/enzyme in the organism has been assigned).

• New Genome Browser: We have made many minor improvements and bug fixes to the new genome browser, Genome Explorer.

• Metabolic Route Search: The display for results of running Metabolic Route Search uses SVG, which did not display correctly on some browsers. We have fixed this issue, such that Route Search now works for all modern Web browers.

• FoldSeek Search: For PGDBs with links to AlphaFold, users can now submit a given protein in the PGDB for a search against all of AlphaFold using FoldSeek -- see right side-bar menu.

Release Notes for BioCyc Version 28.1

Released on August 12, 2024.

Version 28.1 is a minor release that includes updates to the BioCyc website and downloadable data files.

Version 28.1 of BioCyc contains 20,049 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

New Curated Tier 2 Databases for Enterococcus faecalis V583 and OG1RF

The Gram-positive bacterium Enterococcus faecalis is a natural inhabitant of the mammalian gastrointestinal tract and is commonly found in soil, sewage, water, and food, frequently through fecal contamination. It can withstand oxidative stress, desiccation, extremes of temperature and pH, and it has high endogenous resistance to salinity, bile acids, detergents, and antibiotics. It is also an opportunistic pathogen that is becoming increasingly resistant to antimicrobial agents due to acquisition of resistance-conferring mobile genetic elements. Enterococci are resistant to cephalosporins, clindamycin, tetracycline, penicillinase-resistant penicillins such as oxacillin, and vancomycin. In the past decades E. faecalis strains have emerged as the second to third most common cause of nosocomial infections, including urinary tract and soft tissue infections, bacteremia, and endocarditis.

For this release we generated and curated a new Tier 2 database for Enterococcus faecalis V583, the first vancomycin-resistant clinical isolate reported in the United States and the best studied E. faecalis strain. The database includes 220 pathways, 750 enzymes catalyzing 1184 enzymatic reactions, and 292 transporters. Multiple pathways have been revised or created to describe the metabolism of the organism. Some of the topics covered by new pathways are glycerol degradation, extracellular superoxide production, extracellular iron reduction, peptidoglycan biosynthesis, and enterococcal polysaccharide antigen (EPA) biosynthesis and decoration.

In addition to manual curation from the literature, we also imported 2516 transcription start sites (TSSs), 1860 terminators, and 147 small RNAs from a 2020 paper by Michaux et al.

In addition to strain V583, we also created a new database for Enterococcus faecalis OG1RF. Although that database has not been curated methodically like the one for V583, it benefited from ortholog-based propagation of gene functions from the V583 database, and received some manual curation of unique features, including its CRISPR system.

A few examples of curated information from strain V583:

• EPA decoration molecule biosynthesis (part II)
• reactive oxygen species degradation
• glycerol degradation V
• ferric uptake regulator Fur
• ABC family efflux transporter EfrCD
• collagen-binding MSCRAMM adhesin Ace
• endocarditis and biofilm-associated pilus

Updates to MetaCyc Version 28.1

New and Updated Pathways

We have added 39 new pathways to MetaCyc since the 28.0 release and revised 5 existing pathways, for a total of 44 new and revised pathways.

Bacterial Biosynthetic Pathways

We have added 19 new pathways describing biosynthesis of microbial products.

• 3-amino-6-hydroxy-2-piperidone biosynthesis
• 4-acetamido-1H-pyrrole-2-carboxylate biosynthesis
• trans,octacis-decaprenylphospho-β-D-arabinofuranose biosynthesis
• coenzyme A salvage
• cyclic β-1,2-glucan biosynthesis
• cytidine 3'-phospho-5'-diphosphoramidate biosynthesis
• decaprenyl phosphate 5'-methylthioxylose biosynthesis
• indigoidine biosynthesis
• lipoarabinomannan biosynthesis
• lipomannan biosynthesis
• mannose-capped lipoarabinomannan biosynthesis
• MTX-capped lipoarabinomannan biosynthesis
• NAD biosynthesis from nicotinamide II (deamidated pathway)
• netropsin biosynthesis
• oxetanocin A biosynthesis
• spectinomycin biosynthesis
• tRNA-uridine³⁴ modifications (B. subtilis)
• UDP-N-acety-α-D-xylosamine biosynthesis
• venezuelin A biosynthesis

We also revised the following pathways.

• 5-(methoxycarbonylmethoxy)uridine biosynthesis
• pyocyanin biosynthesis

Bacterial Degradation Pathways

• agmatine degradation
• glycerol degradation IV

Other Bacterial Pathways

• selenate reduction I
• selenate reduction II

Cyanobacterial Pathways

• anabaenopeptin A biosynthesis
• anabaenopeptin B biosynthesis
• anabaenopeptin F biosynthesis
• L-homotyrosine biosynthesis
• micropeptin K139 biosynthesis
• oscillamide Y biosynthesis

Plant Pathways

• (19E)-geissoschizine biosynthesis
• akuammicine biosynthesis
• astragaloside biosynthesis
• brucine biosynthesis

Revised pathway:

• strychnine biosynthesis

Fluorescent and Chromo Proteins

• blue chromoprotein chromophore biosynthesis
• cyan fluorescent protein chromophore biosynthesis
• DsRed-type red fluorescent protein chromophore biosynthesis
• green fluorescent protein chromophore biosynthesis
• Kaede-type red fluorescent protein chromophore biosynthesis
• ZsYellow-type yellow fluorescent protein chromophore biosynthesis

Other Eukaryotic Pathways

• dolichol and dolichyl phosphate biosynthesis
• echinocandin B biosynthesis

Other Improvements

Update of EC Reactions

MetaCyc now contains 6830 EC numbers (including internal M numbers).

Updates to EcoCyc Version 28.1

Improvements to the EcoCyc Database

In this version, we annotated regulatory interactions (RIs) for a variety of transcription factors (TFs):

• YegW and YdaT, which were previously considered putative.
• Fur based on RNA-seq and ChIP-seq experiments reported in Hou et al. 2023 and RNA-seq and ChIP-exo experiments reported in Seo et al. 2014.
• Cra from ChIP-exo and RNA-seq analyses reported in Kim et al. 2018.
• KdpE, a href="https://ecocyc.org/gene?orgid=ECOLI&id=EG10482">ZraR, and a href="https://ecocyc.org/gene?orgid=ECOLI&id=EG10020">CpxR from RNA-seq and ChIP-exo experiments reported in Choudhary et al. 2020.

Some of these RIs were further supported by identifying sequences similar to the consensus DNA binding site for each TF.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 28.0

Released on April 2, 2024.

Version 28.0 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 28.0 of BioCyc contains 20,050 Pathway/Genome Databases.

Chrome and Firefox are the recommended web browsers for BioCyc, followed by Safari and Edge. Web browsers are incompatible, they can treat the same web page differently.

1. Improvements to BioCyc Databases

Updates to CyanoCyc

For the Synechocystis PCC 6803 sp. Kazusa Database

Curation from published literature has continued for this database with the addition of

• 4 new pathways, such as the biosynthesis pathways for the polyamines spermidine and putrescine
• 8 new reactions, including biosynthesis of two plastoquinol-9 lipids
• 34 new proteins and complexes, such as subunits for both RNA and DNA polymerases and the protein-RNA complex, the signal recognition particle Ffh protein

We have added 1,389 noncoding and antisense RNAs (ncRNAs and asRNAs, respectively) along with 772 transcription start sites (TSSs) from Mitschke et al. 2011.

For aiding research, we have provided links to external resources for genes that are part of the CRISPRi interference library used by Miao et al. 2023 and for genes that are part of the CyanoSource barcoded mutant library with plasmids that can generate the mutants, mentioned in Mills et al. 2020.

For the Synechococcus elongatus PCC 7942 Database

To aid research associated with S. elongatus PCC 7942, we have provided links for genes that are part of a fluorescence-tagged mutant library, called CyanoTag, available on the morf-db project website (Perrin et al. 2024).

Updates to BsubCyc

For this release we performed significant manual curation of the BsubCyc database. Many gene names and functions were updated to reflect data published in Bremer et al. 2023. The B. subtilis genome contains 54 riboswitches that were previously entered as genes. The riboswitches have been re-curated and now appear as DNA sites. Their display reflects their interaction with a small molecule. Three new pathways have been added:

• tRNA-uridine 2-thiolation
• selenite reduction
• pyruvate fermentation in Bacillus subtilis

Two pathways have been revised:

• nitrate reduction III (dissimilatory)
• methylglyoxal degradation X

Many enzymes have been curated from the literature and received summaries, including the twin-arginine pre-protein translocation (TAT) system; the type VIIb secretion system; the Sec holo-translocon ; the potassium transporters KtrAB, KtrCD, KimA, and KhtSTU); the manganese transporters MneP and MneS and transcriptional regulator for manganese transport MntR; the catalases KatA, KatE and KatX; the branched-chain α-keto acid dehydrogenase system; isocitrate dehydrogenase; autolysin LytD, cyclic nucleotide monophosphate phosphodiesterase PdeB; and the citrate synthases CitA and CitZ. In addition, a subset of the transcriptional regulatory data captured in the DBTBS database (Sierro et al.) was imported from an XML file provided by K. Nakai and Y. Makita. Also, 958 new intrinsic terminators were added based on data published in Mandell et al. 2022.

Updates to Mycobacterium tuberculosis H37Rv Database

This PGDB has undergone a significant curation upgrade since its initial release at the Tier 2 level. Recent updates have focused on extracellular toxins, proteins with immunogenic and immunomodulatory activities, and other virulence factors which contribute to the recognized pathogenic capacity of the species. We have updated the curation of many transporters, serine/threonine protein kinases, type VII secretion systems, the type III-A CRISPR-Cas system, and PE/PPE family proteins. Peptidoglycan biosynthesis pathways have been updated and a new pathway for synthesis of the unusual cell wall sugar 5'-methylthioxylose has been added. We have also described the pathway for the biosynthesis of lipoarabinomannan - a major cell wall constituent of Mycobacterium tuberculosis H37Rv, and associated pathways, including lipomannan biosynthesis, trans,octacis-decaprenylphospho-β-D-arabinofuranose biosynthesis, mannose-capped lipoarabinomannan biosynthesis, and MTX-capped lipoarabinomannan biosynthesis. In addition, we have incorporated information from high-throughput datasets characterizing the transcriptional regulatory network (Rustad et al. 2014, Turkarslan et al. 2015,Minch et al. 2015), over 1000 small RNAs (Stiens et al. 2023, Miotto et al. 2012), 4350 transcription start sites (Cortes et al. 2013, Shell et al. 2015), gene essentiality (461 essential genes and 29 genes with essential domains - DeJesus et al. 2017 and information on anti-tuberculosis compounds.

• type III-A CRISPR-Cas system
• 5'-methylthioxylose
• biosynthesis of lipoarabinomannan
• lipomannan biosynthesis
• trans,octacis-decaprenylphospho-β-D-arabinofuranose biosynthesis
• mannose-capped lipoarabinomannan biosynthesis
• MTX-capped lipoarabinomannan biosynthesis
• Anti-Tuberculosis-Compounds

Updates to EcoCyc Version 28.0

Information from more than 200 publications have been added for this release, which included improvements to various transcription units. Some examples of improvements include:

• The mRNA-degrading endoribonuclease YicC had a structure published that identified the RNA cleavage consensus sequence as GUG and that it exists as a funnel-shaped hexamer (Huang et al. 2023).
• Lee et al. report further characterization of the SoxR-reducing system, suggesting that RsxABCDGE, RseC, and ApbE form a complex that uses NAD(P)H to reduce the SoxR iron-sulfur cluster and a new reaction reflecting this activity has been added to the database.
• We modified 12 terminators from Rho-independent to Rho-dependent based on the publication by Dar and Sorek, 2018.
• We added 22 new Transcription Units (TUs) for small protein coding genes based on their genomic location; they were located on the opposite chromosome strand from the flanking genes or operons. Examples include: yecV, yfiS, yqfH, and ysdE. Furthermore, we included 13 new genes in existing transcription units because they are situated between the genes of the previously annotated TUs.

Updates to MetaCyc Version 28.0

We have added 26_{[more info]} new pathways to MetaCyc since the 27.1 release and revised 2 existing pathway, for a total of 28 new and revised pathways. See the full MetaCyc release notes for a complete discussion of new pathways, EC numbers, and other upgrades.

Improvements to the BioCyc website

Release Notes for BioCyc Version 27.5

Released on December 8, 2023.

Version 27.5 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 27.5 of BioCyc contains 20,043 Pathway/Genome Databases.

Chrome and Firefox are the recommended web browsers for BioCyc, followed by Safari and Edge. Web browsers are incompatible, they can treat the same web page differently.

1. Improvements to BioCyc Databases

New Curated Tier 2 Database for Streptococcus pneumoniae D39V

S. pneumoniae is a major human respiratory pathogen that causes several serious diseases, including pneumonia, meningitis, and septicemia. Strain D39 is an historically important strain that is frequently used in studies of pneumococcal disease. This Pathway/Genome Database (PGDB) was built from a strain known as D39V that was sequenced and comprehensively annotated by the Veening group at the University of Groningen (Slager et al. 2018). The database includes imported transcription-start sites, terminators, and ribosome binding sites from (Slager et al. 2018). The database has undergone significant manual curation focusing on key areas of pneumococcal biology (example curated pathways and genes are noted):

• Energy production – mixed acid fermentation; homolactic fermentation
• Host sugar degradation – complex N-linked glycan degradation; high-mannose N-linked glycan degradation
• Extracellular polysaccharide production – capsular polysaccharide biosynthesis; teichoic acid biosynthesis
• Quorum-sensing systems including the competence pathway (see peptide pheromone BlpC, competence-stimulating peptide and other related proteins) and Rgg/SHP type systems
• Surface proteins such as the chloine-binding proteins, including CbpA, PcpA, CbpD, and CbpE, and other virulence-related surface proteins including PavA, PavB
• The major murein hydrolases LytA, LytB, and LytC which play roles in autolysis, cell division and competence induced fratricide, respectively
• Restriction-modification systems, e.g., phase-variable Type I R-M system SpnD39III
• Peptidoglycan biosynthesis

Curated gene and protein annotations were propagated from Streptococcus pneumoniae D39V to orthologs in the 234 other S. pneumoniae PGDBs in BioCyc, with each PGDB receiving updates to an average of 300 genes or proteins. Propagated data included gene and protein names, protein complex assignments, and the reactions assigned to each protein.

New Curated Tier 2 Database for Klebsiella pneumoniae NTUH-K2044

Like E. coli, K. pneumoniae is a member of the gammaproteobacterial family Enterobacteriaceae. It is recognized by both the Infectious Diseases Society of America (IDSA) and the World Health Organisation (WHO) as an ESKAPE pathogen (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) -— a globally relevant priority list of clinically significant antibiotic-resistant bacteria. Infections caused by K. pneumoniae range from mild to severe and antibiotic-susceptible to extensively drug-resistant, and can include urinary tract infections (UTIs), pneumonia, wound infections, bloodstream infections (BSIs) and liver abscesses, among others. The genome used to build this Pathway/Genome Database (PGDB) belongs to a clinical hypervirulent strain isolated from a patient with a liver abscess and meningitis. Key areas of manual curation for the database include:

• Siderophore biosynthesis (yersiniabactin, salmochelin and aerobactin)
• The type VI secretion system
• Metal resistance determinants (copper, silver and tellurium)
• Serotype K1 capsular polysaccharide biosynthesis
• O1 antigen synthesis genes (rfbA, rfbB, wbbM, rfbD, wbbN, wbbO)
• Outer membrane proteins (OmpA, OmpK26, OmpK35, OmpK36, OmpK37, OmpK38, LamB and PhoE)
• The type I-E* CRISPR-Cascade complex and the Cas1-Cas2 integrase complex
• Type 1 fimbriae and type 3 fimbriae

Curated gene and protein annotations were propagated from Klebsiella pneumoniae pneumoniae NTUH-K2044 to orthologs in the 179 other K. pneumoniae PGDBs in BioCyc, with each PGDB receiving updates to an average of 202 genes or proteins. Propagated data included gene and protein names, protein complex assignments, and the reactions assigned to each protein.

Improvements to the Synechocystis sp. PCC 6803 substr. Kazusa Database

The curated database for Synechocystis sp. PCC 6803 released in Aug 2023 has since been reviewed and updated by a panel of eight cyanobacterial researchers to ensure high-quality data. These researchers, listed as coauthors on the database Summary Statistics page, contributed expertise in fields such as biosynthetic pathways, electron transport reactions, and pilus proteins. Some notable new additions include:

• Several representations of electron transport pathways, such as the superpathway of electron transport in the thylakoid membrane and in the plasma membrane and linear electron flow through plastocyanin and through cytochrome c₆
• Proteins involved in the glycan biosynthesis pathway: 1,4-alpha-glucan branching enzyme and two glycogen synthase proteins, GlgA1 and GlgA2
• The type IV plus and related proteins including the inactive, frameshifted type IV plus platform protein, implicated in the non-motility of the Kazusa strain

Improvements to the Corynebacterium glutamicum ATCC 13032 Database

We imported 1698 transcription start sites into this database from Pfeifer-Sancar et al. (2013).

Updates to EcoCyc Version 27.5

The EcoCyc data have been curated from 39,425 publications. EcoCyc includes the equivalent of 4012 textbook-pages of mini-review summaries.

For this release of the EcoCyc database, we have curated new pathways and reactions, new functions for existing proteins and small RNAs, and new regulatory interactions:

• In order to better represent the various ways that tRNAs undergo nuclease-based processing, we have created 3 new pathways: monocistronic tRNA processing I, II, and III. The new pathways represent how monocistronic tRNA genes are processed differently from each other and from polycistronic tRNA genes for how the ribonuclease enzymes cleave the 5’ and 3’ extensions to yield the uncharged tRNA ready for addition of its cognate amino acid.
• Yang et al. have characterized LptM (formerly YifL) as a new player in the lipopolysaccharide transport (Lpt) pathway; LptM interacts physically with the outer membrane LPS translocon and promotes its assembly by the BAM complex.
• A new transport function has been added to ThrP (formerly YifK), characterized by Khozov et al. as a PMF-dependent L-threonine and L-serine transporter.
• The function of ABC transporter CydDC has long been debated. Using a combination of biochemical, structural and computational methods Wu et al. have now confirmed its role as a heme transporter that is required for maturation of cytochromes bd-I and bd-II.
• We curated a publication of an integrative study reporting data from ChIP-exo and RNA-seq methodologies for the transcription factor Fur (Gao et al.): 56 new regulatory interactions for Fur were added and 67 were updated. Most of the regulatory interactions from this publication have been annotated, and the remaining ones that require further analysis will be available in the next release.
• Additional curation resulted in summary updates for 33 transcription factors, 3 sigma factors (RpoS, RpoH, and RpoD) and 4 small regulatory RNAs (DsrA, RyhB, and OxyS).

2. New in the BioCyc Website

• New Genome Browser: We have re-implemented the Genome Browser in JavaScript. The new version looks much like the old version, but it is much faster -- it zooms and pans in real time (zoom with your mouse wheel or trackpad), which is a major improvement to the user experience. And the new version has a sequence-selection capability, both for nucleotide and amino-acid sequences. Invoke this tool using Tools → Genome → Genome Browser, and click the Quick Help button for more information. The old genome browser is available in the same menu.
  New Genome Browser examples:
  
  • Single genome browse for Escherichia coli K-12 or for Streptococcus pneumoniae D39V
    
  • Comparative browse

• BLAST Search Enhancements: We have made multiple improvements to the BLAST search results page. We have also modified BLAST searches so that the user can now perform a BLAST search against a set of BioCyc organisms specified in a SmartTable (such as against a representative set of cyanobacteria).

• Sequence Pattern Search Enhancements: We have modified sequence pattern searches so that the user can now perform a pattern search against a set of BioCyc organisms specified in a SmartTable.

• Multi-Omics Cellular Overview: The multi-omics painting capabilities of the Cellular Overview (metabolic map diagram) has been expanded so that the diagram can be painted with up to four omics datasets simultaneously. Data can be painted onto node color and size, and onto edge color and size. For example, the user could display a transcriptomics dataset, a proteomics dataset, and two metabolomics datasets simultaneously. To run this tool, first display the Cellular Overview with the command Tools → Metabolism → Cellular Overview; then run the command Upload Multi-Omics Data from File in the right-sidebar menu.

• Improvements to Omics Dashboard: The Omics Dashboard has been extended to support multi-omics datasets with either two or three component datatypes, for example, transcriptomics, metabolomics and proteomics data. The aggregated data for each subsystem from all component datasets is combined into a single plot (with dual Y-axes), so that all types of data for a subsystem can be viewed side-by-side. Other significant extensions to the Omics Dashboard include a new data filtering module with multiple filter options, and the ability to customize the colors used for each data column.

• Accessibility Improvements: We have made many improvements to the accessibility of the Navigator for disabled persons.

Release Notes for BioCyc Version 27.1

Released on August 28, 2023.

Version 27.1 is a minor release that includes updates to the BioCyc website and downloadable data files.

Version 27.1 of BioCyc contains 20,042 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

New Curated Tier 2 Database for Synechocystis sp. PCC 6803 substr. Kazusa

Synechocystis sp. PCC 6803 is a unicellular, non-nitrogen-fixing, freshwater cyanobacterium that was isolated in 1968 from a lake at Berkeley, California. The original strain does not tolerate glucose in the light. However, as the organism is naturally competent and transformable by exogenous DNA, glucose-tolerant substrains allowing photoheterotrophic, mixotrophic, and heterotrophic growth were constructed. A glucose-tolerant (GT) strain known as GT-Kazusa (full name Synechocystis sp. PCC 6803 substr. Kazusa) was sequenced in 1996, making it the first cyanobacterium and the fourth organism to have its chromosome completely sequenced.

In addition to the polyploid chromosome the organism has seven plasmids - four large ones (pSYSM/120 kb; pSYSX/106 kb; pSYSA/103 kb; pSYSG/44 kb) and three small ones (pCA2.4/2.4 kb; pCB2.4/2.4 kb).

Synechocystis sp. PCC 6803 is one of the most extensively studied cyanobacterial species. The biochemical similarities between plant chloroplasts and the organism make it an ideal system for studying the molecular mechanisms underlying stress responses and stress adaptation in higher plants. The cyanobacterium has also been used extensively as a host for metabolic engineering and synthetic biology studies.

This PGDB was constructed from the RefSeq annotation for the chromosome and plasmids and has undergone significant manual curation based on the literature. This work included authoring of summaries and assignment of evidence codes describing the functions of more than 200 genes. Further curation will continue to be performed in the coming months.

A few examples of curated entries include:

Enzymes

• sensor histidine kinase CopS
• bidirectional hydrogenase
• photosystem II
• phycobilisome
• β-carboxysome
• β-carotene hydroxylase
• 6-hydroxymethylpterin-β-galactoside glucuronosyltransferase

Pathways

• glucosylglycerol biosynthesis
• ophthalmate biosynthesis
• phycocyanobilin biosynthesis
• oleate biosynthesis
• 3,8-divinyl-chlorophyllide a biosynthesis III (aerobic, light independent)
• NADPH to cytochrome c oxidase via plastocyanin (thylakoid membrane)
• galactolipid biosynthesis
• superpathway of phylloquinol biosynthesis

Updates to MetaCyc Version 27.1

New and Updated Pathways

We have added 23_{[more info]} new pathways to MetaCyc since the last release and revised 1 existing pathway, for a total of 24 new and revised pathways.

Bacterial Biosynthetic Pathways

A new pathway describes the biosynthesis of poly-β-1,6-N-acetyl-D-glucosamine (PNAG), an exopolysaccharide that is a key component of the biofilm matrix of many pathogenic bacteria. Two new pathways describe the biosynthesis of the capsular polysaccharides of the two most important Streptococcus pneumoniae serovars. Another pathway describes the production of UDP-N-acetyl-α-D-mannosamine, a component of many bacterial and archaeal polysaccharides.

• poly-β-1,6-N-acetyl-D-glucosamine biosynthesis
• Streptococcus pneumoniae serotype 2 capsular polysaccharide biosynthesis
• Streptococcus pneumoniae serotype 4 capsular polysaccharide biosynthesis
• UDP-N-acetyl-α-D-mannosamine biosynthesis

Bacterial Degradation Pathways

A new pathway describes the activity of the recently discovered enzyme EC 4.3.1.33, (R)-1-hydroxy-2-aminoethylphosphonate ammonia-lyase, an enzyme with a narrow substrate specificity which expands the range of phosphonates known to be utilized by bacteria. Many Gram-negative bacterial species carry plasmids such as R773, which contains the arsABCD genes for arsenate detoxification (that process is described in arsenate detoxification I). Some organisms, such as E. coli MG1655, do not carry such a plasmid and rely on chromosomal genes, as described by a new pathway for arsenate detoxification. The marine bacterium Pseudoalteromonas sp. CF6-2 can kill a variety of Gram-positive bacteria by attacking their cell-wall peptidoglycan and can use the liberated D-glutamate as its sole carbon and nitrogen source as described in a new D-glutamate degradation pathway. A new pathway describes how bacteria can convert glycine to pyruvate and ammonium, satisfying the need for both carbon and nitrogen (this pathway is also a part of the photorespiration pathway found in higher plants). Another new pathway describes the degradation of the toxic compound methylglyoxal by the enzyme glyoxalase III (officially named EC 4.2.1.130, D-lactate dehydratase), which converts methylglyoxal to (R)-lactate in a single step.

• (1R)-(2-amino-1-hydroxyethyl)phosphonate degradation
• arsenic detoxification XI
• D-glutamate degradation
• glycine degradation
• L-cysteine degradation IV
• methylglyoxal degradation IX

Plant Biosynthetic Pathways

The kavalactones are known for their psychoactive effects and have pharmaceutical potentials for treating anxiety, insomnia and pain. This pathway describes the use of a cloned styrylpyrone methyltransferase from the kava plant to produce kavalactones in E. coli.

• 5,6-dehydrokavain biosynthesis (engineered)

Fungal Biosynthetic Pathways

The sphingofungins are a group of structurally related compounds produced by fungi that specifically inhibit EC 2.3.1.50, serine C-palmitoyltransferase, the enzyme that catalyzes the initial step in sphingolipid biosynthesis. This new pathway describes the biosynthesis of sphingofungins B, C, and D by the human pathogenic fungus Aspergillus fumigatus.

• sphingofungin B-D biosynthesis

Electron Transfer Pathways

We have added four new electron transfer pathways characterized from the opportunistic pathogenic bacterium Staphylococcus epidermidis.

• glycerol 3-phosphate to cytochrome aa₃ oxidase electron transfer
• NADH to cytochrome aa₃ oxidase electron transfer
• NADH to nitrate electron transfer
• succinate to cytochrome aa₃ oxidase electron transfer

Archaeal Pathways

Tetrahydromethanopterin and tetrahydrosarcinapterin are alternatives to folate used by members of the archaea. A new pathway describes the latter part of the methanogenesis process in organisms that produce tetrahydromethanopterin. Another pathway describes the production of tetrahydrosarcinapterin by the ATP-dependent glutamylation of tetrahydromethanopterin.

• methyl-coenzyme M oxidation to CO₂ II
• tetrahydrosarcinapterin biosynthesis

Mammalian Pathways

Aspartame is a low-calorie sweetener used extensively worldwide in a wide variety of foods and beverages. A new pathway describes its degradation in the mammalian intestine. Human milk oligosaccharides are abundant carbohydrates fundamental to infant health and development. They account for 11-17% of the milk. More than a hundred different oligosaccharides have been characterized from human milk; a new pathway describes the biosynthesis of the most common ones.

• aspartame degradation
• human milk oligisaccharides biosynthesis

Salvage Pathways

Eukaryotes produce NAD de novo from L-tryptophan. A new eukaryotic pathway describes the phosphorylation of the vitamin B3 compound β-D-ribosylnicotinate (nicotinate riboside), which allows its salvage for production of NAD. Another salvage pathway describes the conversion of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole-2-carboxylate, a degradation product of an intermediate in thiamine diphosphate biosynthesis, back to thiamine diphosphate.

• nicotinate riboside salvage pathway I
• thiamine diphosphate salvage V

Other Pathways

Aminoacyl-tRNA synthetases join amino acids with their cognate tRNAs in high fidelity reactions that define the genetic code. Most of these enzymes are specific for a particular amino acid. The reaction starts by activation of the amino acid to an adenylate form, which is is initially held noncovalently in the active site before being transferred to the 2' or 3' hydroxyl group of the terminal ribose of the tRNA. The fidelity required to ensure proper protein biosynthesis is estimated to be 1 in 3300. However, many of the enzymes are not specific enough during the adenylation step, resulting in activation of the wrong amino acid at a rate that is too high. To ensure proper protein synthesis, mechanisms known as "editing" exist for the release of misacylated amino acids before they are transferred to the tRNA.

• misacylated tRNA editing

Updated Pathways

The following pathways have been modified to reflect new information that has become available since they were last curated.

• diadinoxanthin and fucoxanthin biosynthesis (diatoms)

Other Improvements

Update of EC Reactions

During this quarter we have updated the Enzyme Commission (EC) definitions in MetaCyc with the latest information (as of August 2023) from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) and the Joint Commission on Biochemical Nomenclature (JCBN), available from the ExplorEnz database. MetaCyc now contains 6698 EC numbers (including internal M numbers).

Updates to EcoCyc Version 27.1

Improvements to the EcoCyc Database

Several new pathways and reactions were added:

• Misacylated tRNA editing pathway: Aminoacyl-tRNA synthetases (AARS) join amino acids with their cognate tRNAs in high fidelity reactions that define the genetic code. Most of these enzymes are specific for a particular amino acid. The reaction starts by activation of the amino acid in the AARS active site to an adenylate form before being transferred to the 2' or 3' hydroxyl group of the terminal ribose of the tRNA. The fidelity required to ensure proper protein biosynthesis is estimated to be 1 in 3300. However, 10 of the 24 AARS families cannot achieve the tolerable level of fidelity. To ensure proper protein synthesis, two "editing" mechanisms by different AARSs exist, such as:
  • a pre-transfer editing reaction

  • a post-transfer editing reaction

• All of the aminoacyl-tRNA synthetases that have editing capabilities and the mischarged aminoacyl-tRNA deacylase (YeaK) reactions were added as well as text to their summaries to describe their editing activities.
• A new pathway (poly-β-1,6-N-acetyl-D-glucosamine (PNAG) biosynthesis) describes the biosynthesis of PNAG, an exopolysaccharide that is a key component of the biofilm matrix of many pathogenic bacteria.
• The new glycine degradation pathway describes how bacteria can convert glycine to pyruvate and ammonium, satisfying the need for both carbon and nitrogen.
• The thiamine diphosphate salvage V pathway describes the conversion of 5-(2-hydroxyethyl)-4-methyl-1,3-thiazole-2-carboxylate, a degradation product of an intermediate in thiamine diphosphate biosynthesis, back to thiamine diphosphate.

Significant upgrades to major nucleotide binding and cell division proteins:

• The Hfq is a major global regulator of cell physiology. With the addition of information from 88 publications we have updated the summary to include descriptions of its many functions within the cell. The regulatory aspects of Hfq have expanded beyond its major role as a post-transcriptional regulatory factor of small RNAs and their mRNA targets to include roles in ribosome biogenesis, tRNA processing and possibly regulation of DNA replication and compaction. Additional protein-protein and protein-lipid interactions of Hfq also have been documented.
• The bacterial condensin protein complex, MukBEF , an ATPase-powered molecular machine, is involved with the global organization of E. coli’s chromosome and its segregation during cell division. The summaries of this complex and its different subunits have also been upgraded with information from 24 publications to highlight their distinct roles in the function of chromosome organization.
• The cell division protein FtsZ is a highly conserved protein essential to forming the Z-ring site where cell division will occur. Addition of information from 23 publications rounds out the information about this important “wrangler” of proteins.
• Another important wrangler of proteins involved in assembling the divisome is FtsA, which had experimental information from 17 articles added to its summary.

Additional upgrades of note include:

• Modification of the DNA binding consensus sequence of the : two conserved motifs that were previously considered independent sites are now part of a single site.
• Extensive editing of the Suf system components, particularly , which went from 4 wrong reactions to two correct ones.
• Small Long Direct Repeat (LDR) toxic polypeptides: LdrA,B,C and D.
• Significant changes were made to the commentary of two fatty acid beta-oxidation complexes (aerobic FAO and anaerobic FAO), and reactions were assigned.
• Extensive editing of , and were done.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 27.0

Released on April 12, 2023.

Version 27.0 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 27.0 of BioCyc contains 20031 Pathway/Genome Databases.

Chrome and Firefox are the recommended web browsers for BioCyc, followed by Safari and Edge. Web browsers are incompatible, they can treat the same web page differently.

1. Improvements to BioCyc Databases

New Curated Tier 2 Database for Staphylococcus epidermidis RP62A

Staphylococcus epidermidis is known as a dominant commensal microbial species of the human skin and mucous membranes, and can also be found in association with various other mammals. Colonization by S. epidermidis in healthy adults is usually harmless. However, in recent decades, the species has been recognised as a significant cause of opportunistic and sometimes multidrug-resistant nosocomial infections due to its adherence to various types of implanted medical devices—such as prosthetic joints and intravascular catheters—and its subsequent persistence within biofilms.

This PGDB uses the RefSeq annotation of the biofilm-producing and methicillin-resistant strain S. epidermidis RP62A, and has undergone significant manual curation in key areas such as biofilm formation, virulence, electron transport and metabolism. This work included authoring of summaries and assignment of evidence codes describing the functions of more than 100 genes encoding proteins or small RNAs (sRNAs). Additionally, information from manually curated genes with experimental evidence codes in S. epidermidis RP62A was computationally transferred to 58 other S. epidermidis BioCyc PGDBs via ortholog propagation.

A few examples of curated entries include:

• Major virulence and biofilm-associated cell wall anchored (CWA) surface proteins such as Aap, AtlE, EmbP, Sbp, SesA-SesHY, and the microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) SdrF and SdrG
• The type III-A CRISPR-Cas adaptive immune system, including the CRISPR locus, the Cas10-Csm complex, and the Cas1-Cas2 integrase complex
• The UDP-GlcNAc synthesis proteins GlmS, GlmM and GlmU and the peptidoglycan synthesis proteins MurA1 and MurB

New Curated Tier 2 Database for Alteromonas macleodii ATCC 27126

We have curated the type strain of the ubiquitous marine copiotroph, Alteromonas macleodii, known to be an important part of the marine microbial community and increasingly important model organism. The curation was a collaborative effort at a workshop at the University of Haifa, Israel, in Feb 2023. During this "curate-a-thon" 60 proteins had evidence provided from the literature, 42 unique citations were added along with 41 new reactions, 7 new pathways and 1 superpathway, and more than 1000 protein features were imported.

Highlights of the curation include:

• Creation of a pectin degradation pathway illustrating the various ways that A. macleodii can utilize this complex polysaccharide
• Identification of the nitrate reductase and nitrite reductase genes and reactions
• The urate hydroxylase gene and its role in the urate conversion to allantoin III pathway
• The complete petrobactin biosynthesis pathway

Updates to MetaCyc Version 27.0

MetaCyc now contains 3085 metabolic pathways from all domains of life. MetaCyc contains the equivalent of 10,392 textbook-pages of mini-review summaries.

We have added 24 new pathways to MetaCyc since the last release and revised 2 existing pathways, for a total of 26 new and revised pathways.

Bacterial pathways

• 1-(sn-glycero-3-phospho)-1D-myo-inositol biosynthesis
• 2-O-(β-D-mannosyl-(1→2)-β-D-mannosyl)-bis(myo-inositol) 1,3'-phosphate biosynthesis
• 2-oxoglutarate-derived opine biosynthesis
• corallopyronin A biosynthesis
• furaquinocin biosynthesis
• mannopine and agropine biosynthesis
• poly-γ-D-glutamate biosynthesis
• pyruvate-derived opine biosynthesis I (bacteria)
• 4-hydroxypyridine degradation
• carminate degradation
• D-alanine degradation
• L-fucose degradation II
• L-mimosine degradation
• mammalian high-mannose N-glycan degradation
• puerarin degradation
• yeast mannan degradation

Archaeal pathways

• 1-(sn-glycero-1-phospho)-1D-myo-inositol biosynthesis
• nucleoside and nucleotide degradation (halobacteria)

Fungal pathways

• (4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine biosynthesis
• cyclosporin A biosynthesis

Plant pathways

• cucurbitacin biosynthesis
• hyperxanthone E biosynthesis

Metazoan pathways

• carminate biosynthesis
• blood coagulation - tissue factor pathway

The following two pathways have been modified to reflect new information that has become available since they were last curated.

• salicortin biosynthesis
• t-anethole biosynthesis

Updates to EcoCyc Version 27.0

The EcoCyc data have been curated from 38835 publications. It includes the equivalent of 3844 textbook-pages of mini-review summaries.

Multiple new genes, including two new proteins and several small RNAs, and new functions for existing proteins have been added and curated with summaries for each new gene product and regulatory interactions for the small RNAs with functions identified.

New genes:

• The new small protein, XtpA, is a putative transcription regulator of genes involved in aminoglycoside antibiotic resistance through regulation of the small regulatory RNA GcvB
• Another new small protein, SpfP, was characterized and found to tightly bind and regulate the CRP-cAMP transcription factor. It is encoded by the same transcriptional unit as spf which codes the small regulatory RNA Spot 42

New small RNAs added to EcoCyc:

• FimR2, reported by Raad et al. to be a significant regulator of gene expression in stationary phase
• GlnZ was found to modulate a variety of genes under low nitrogen conditions
• aMEF stimulates expression of the type II mazEF toxin-antitoxin system
• StfZ represses the transcriptional regulator FtsZ affecting other genes involved in cell division
• AsflhD represses the transcriptional regulator FlhD affecting mobility
• three small antisense RNAs were identified but no function assigned: (AsCRP, AsompR, AsphoP)

New gene functions curated:

• The 5′-3′ exoribonuclease RNase AM encoded by rnmhas been found to have FAD-capped RNA decapping (deFADding) and degradation functions
• A new NAD(P)H oxidation reaction that produces hydrogen peroxide and superoxide radical under aerobic conditions was ascribed for SthA
• A new function added to the outer membrane protein PqqU (formerly yncD), characterized by Hantke et al. as a TonB-dependent transporter of the redox cofactor pyrroloquinoline quinone
• The function of YdiJ has been characterized as a D-2-hydroxyglutarate dehydrogenase (D2HGDH) than can metabolize the D-2-hydroxyglutarate (D-2-HGA) produced by SerA
• A new function for ZapG (also called LapD) indicates it plays a role in cell envelope homeostasis by possibly regulating LpxC levels and aiding in MsbA-mediated LPS translocation
• The iron-sulfur cluster repair protein YtfE has a new function as a nitric oxide (NO)-generating nitrite reductase

Other updates include:

• Confirmation that FimZ is a transcription factor by Ogawa et al., and four regulatory interactions were annotated for it.
• 60 new regulatory interactions of the transcription factor CpxR as a result of qRT-PCR, cpxR knockout mutant, DNA binding analysis and computational predictions; see Zhao et al.
• Four new inactive conformations of the transcription factor AcrR were included.
• Changes to evidence codes and the evidence ontology resulting in 14 new evidence codes and 6 reclassified ones that are now used in curation. These evidence codes refer to specific experimental methodologies, both classical and high throughput methods.

2. New in the BioCyc Website

• Comparative Genome Dashboard: This new tool enables visual comparisons of the complete cellular machineries of multiple BioCyc organisms. It provides both broad comparisons of many cellular subsystems as well as the ability to drill down through multiple levels of detail to examine the presence and absence of genes and pathways. Invoke this tool as Tools → Analysis → Comparative Genome Dashboard. [Example]
• Omics Data Table Viewer: This new tool provides a tabular view of transcriptomics and metabolomics datasets to complement the other omics data tools in BioCyc. Clicking on columns in the table enables sorting of the data by multiple criteria. Invoke this tool from the right-sidebar menu of the Cellular Overview when this diagram is painted with omics data.

Release Notes for BioCyc Version 26.5

Released on December 13, 2022.

Version 26.5 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 26.5 of BioCyc contains 20028 Pathway/Genome Databases.

Chrome and Firefox are the recommended web browsers for BioCyc, followed by Safari and Edge. Web browsers are incompatible, they can treat the same web page differently.

1. Improvements to BioCyc Databases

Staphylococcus aureus aureus NCTC 8325 updated.

This PGDB has undergone a significant curation upgrade since its initial release at the Tier 2 level. Recent updates have focused on a large number of extracellular toxins and other virulence factors which contribute to the recognized pathogenic capacity of the species (see for example alpha-hemolysin, delta-hemolysin and epsilon-cytotoxin). We have also added over 250 small RNA-encoding genes as described by Carroll et al (2016), and updated the curation of many transporters, respiratory enzymes, DNA repair proteins, and stress-response proteins.

Updates to MetaCyc Version 26.5

MetaCyc now contains 3085 metabolic pathways from all domains of life. MetaCyc contains the equivalent of 10,392 textbook-pages of mini-review summaries.

New and Updated Pathways

We have added 22 new pathways to MetaCyc since the last release. We also added one superpathway, for a total of 23 new pathways.

Bacterial Lipopolysaccharide Biosynthetic Pathways

Lipopolysaccharides (LPS) are complex compounds that can be conceptually divided into three parts: lipid A, which anchors LPS into the membrane; the core oligosaccharide, which contributes to membrane stability; and the O-antigen, which is a polysaccharide that extends away from the cell surface. Each part is a complex large molecule on its own. In order to facilitate the representation of their biosyntetic pathways, these complex pathways have been broken into a series of shorter pathways focusing on one aspect of the process, such as lipid A biosynthesis, core oligosaccharide biosynthesis, and O-antigen biosynthesis. For this release we added several pathways describing the last step in the process - the attachment of the O-antigen to the lipid A-core oligosaccharide complex.

• Brucella abortus lipopolysaccharide biosynthesis (final steps)
• Helicobacter pylori 26695 lipopolysaccharide biosynthesis (final steps)
• Porphyromonas gingivalis lipopolysaccharide (O-LPS) biosynthesis (final steps)
• Salmonella typhimurium LT2 lipopolysaccharide biosynthesis (final steps)

Biosynthesis of Polyketide Extender Units

Polyketides are secondary metabolites produced by some bacteria, fungi, plants, and animals. They are usually biosynthesized by polyketide synthase enzymes (PKS) through the decarboxylative condensation of extender units that are derived from malonyl-CoA, in a process similar to fatty acid synthesis. The biosynthesis of some polyketides involves unusual extender units, which are produced by their own specialized pathways. We added new pathways that describe the biosynthesis of three unusual extender units.

• (2R)-methoxylmalonyl-[acp] biosynthesis
• (2S)-ethylmalonyl-CoA biosynthesis
• 2-allylmalonyl-CoA biosynthesis

Fungal Biosynthetic Pathways

We added four new pathways that describe the biosynthesis of fungal products. Ascomycin is a macrocyclic polyketide produced by Streptomyces hygroscopicus subsp. ascomyceticus that acts as a potent immunosuppressant that prevents T-cell proliferation. The cyathins are a family of compounds produced by fungi belonging to the genus Cyathus (bird's nest fungi), many of which show interesting biological activities. Like the cyathins, the erinacines are based on a cyathane skeleton, but they are modified with a xylose sugar. Many of the erinacines also demonstrate unique biological activities, such as potent stimulating activity for nerve-growth-factor synthesis and agonistic activity towards the kappa opioid receptor. Fumigillin is a meroterpenoid compound produced by the mold Aspergillus fumigatus that has been studied for its anti-angiogenic properties. It also has pharmaceutical potential for the treatment of microsporidiosis, and is the only effective chemical treatment currently available for honey bee nosemiasis, which is caused by parasitic fungi from the Microsporidia phylum.

• ascomycin biosynthesis
• cyathin biosynthesis
• erinacine biosynthesis
• fumagillin biosynthesis

Bacterial Degradation Pathways.

N-(1-deoxy-D-fructos-1-yl)-L-asparagine (F-Asn) is an Amadori product - a type of compound that is formed spontaneously by the interaction of a reducing sugar (such as glucose and fructose) with a biological amine such as an amino acid, followed by a rearrangement to form a stable ketoamine. F-Asn occurs naturally in substantial quantities in foods, particularly after heating. We added a pathway describing its degradation by bacterial species such as Salmonella enterica, which uses F-Asn as its primary nutrient in the inflamed intestine. Another new pathway describes a cysteine salvage pathway acting on benzylated cysteine. L-canavanine is a plant product that serves as an antimetabolite of L-arginine and is involved in plant defense. Despite its toxicity it serves as a signaling molecule for free-living symbiotic bacteria to onset their symbiosis with the legume plant, and as a nutrient for bacteria living in the rhizosphere.

• N-(1-deoxy-D-fructos-1-yl)-L-asparagine degradation
• S-benzyl-L-cysteine degradation
• L-canavanine degradation II

Other Bacterial Biosynthetic Pathways

The pentitol sugar ribitol is a common component of teichoic acids and capsular polysaccharides of Gram-positive bacteria. The compound is transferred to the growing polymers from its activated form, CDP-ribitol.

• CDP-ribitol biosynthesis

Archaeal Pathways

Glycerol dialkyl glycerol tetraether lipids (GDGTs) are a class of membrane lipids synthesized by many archaea (and some bacteria). They are formed by the joining together of two archaeol-type phospholipids, and because they have two hydrophilic head groups, they form a lipid monolayer in the cell membrane instead of a bilayer, making GDGT-producing organisms exceptional among all clades of life. Macrocyclic archaeol phospholipids are generated by the same enzyme that forms GDGTs. However, in this case rather than connecting two archaeol molecules to each other, the enzyme ligates the ends of the two phytanyl chains to each other, cyclyzing the archaeol molecule.

• glycerol dibiphytanyl glycerol tetraether lipid biosynthesis
• macrocyclic archaeol phospholipid biosynthesis

Mammalian Pathways

All mammals appear to operate a glycolysis pathway from fructose at some capacity, but the pathway plays a key role in the metabolism of the naked mole-rat under low oxygen conditions. These animals tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain via a glycolysis pathway.

• glycolysis VI (from fructose)

Icosanoids Biosynthesis

Polyunsaturated fatty acids (PUFAs) can be oxygenated either enzymatically or in free radical-mediated reactions into hundreds of oxygenated species, many of which are mediators of cellular processes. The best-studied classes of these oxygenated mediators are the icosanoids (sometimes spelled eicosanoids). Even though the name is derived from the ancient Greek word eikosi, which means twenty, to signify the 20 carbons present in arachidonate-derives compounds, it is often used for metabolites of 18- and 22-carbon PUFAs. We added several pathways that integrate reactions that form the PUFAs by releasing them from lipids and steroids and reactions that show the most common transformations of those PUFAs into icosanoids.

• representative whole plasma arachidonate-derived icosanoids I
• representative whole plasma arachidonate-derived icosanoids II
• representative whole plasma DHA-derived icosanoids
• representative whole plasma EPA-derived icosanoids

Superpathways

Cardiolipin is one of the three most common glycerophospholipids found in bacteria. Although MetaCyc already contained several pathways describing cardiolipin biosynthesis, we have added a new superpathway that integrates several of these pathways, as well as pathways forming precursors used in cardiolipin biosynthesis.

• superpathway of cardiolipin biosynthesis (bacteria)

Other Improvements

Update of EC Reactions

During this quarter we have updated the Enzyme Commission (EC) definitions in MetaCyc with the latest information (as of October 2022) from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) and the Joint Commission on Biochemical Nomenclature (JCBN), available from the ExplorEnz database. MetaCyc now contains 6658 EC numbers (including internal M numbers).

Updates to EcoCyc Version 26.5

The EcoCyc data have been curated from 42,768 publications. It includes the equivalent of 3825 textbook-pages of mini-review summaries.

We have curated the previously uncharacterized protein, YmdF, based on recent work by Kaleta et al. 2022, which indicates this protein is likely involved in motility, biofilm formation and susceptibility to a variety of antimicrobial agents.

We also curated regulatory interactions for YiaU and YgfI confirming their role as transcription factors, and their regulation of specific processes was described in the summaries.

In this release summaries were added for 58 putative transcription factors that include properties such as their protein family, the domain for DNA binding, some putative processes that they regulate, and how they are regulated (CITS:35880217).

We included five new inactive conformations of transcription factors: AcrR-3,6-diaminoacridine (proflavin), AcrR-rhodamine 6G (RDG), Cbl-thiosulfate, MurR-N-acetyl-D-glucosamine-6-phosphate and AraC-D-fucose.

New DNA-binding consensus sequences for five sigma factors were added.

New structural insights into several proteins involved in cell division were curated, including FtsQBL and FtsA-FtsZ, as well as additional structural characterizations for PsuK, IaaA, and GyrA.

2. New in the BioCyc Website

• New pathway search tool: (Tools → Search → Search Pathways) enables searching for pathways based on a set of metabolites and gene names entered by the user. The result pathways are ranked by the number of matches.

• Sequence pattern search tool: This tool (Tools → Search → Sequence Pattern Search) now provides expanded search options. In addition to searching the entire genome or proteome of a given organism, the tool can search all proteins within a provided SmartTable, and can search the entire proteomes of a set of organisms provided in an organism SmartTable.

• When painting omics data onto the Cellular Overview (metabolic network) tool, a new Data Table Viewer enables the user to send the omics data to a tabular viewer tool, such as to enable sorting of the omics data by omics data value. The entire omics dataset can be sent to this table viewer, or the user can send all data from a given pathway category (e.g., Amino Acid Biosynthesis).

• The "Change Current Database" tool now searches an expanded set of organism names.

• If you create a SmartTable of BioCyc organisms, you can now use the SmartTables operation "add property column" to examine organism metadata for the organisms. To create an organism SmartTable, go to a gene page and then click "Change Organisms/Databases for Future Comparison Operations" in the right-sidebar menu.

• Circular Genome Viewer: This tool can now display data tracks from an uploaded GFF file.

• When searching a PGDB for chemical substructures, substructures can now be drawn using the JSME editor (see Tools → Search → Search Compounds).

Release Notes for BioCyc Version 26.1

Released on August 24, 2022.

Version 26.1 is a minor release that includes updates to the BioCyc website and downloadable data files.

Version 26.1 of BioCyc contains 20,011 Pathway/Genome Databases. A total of 11 new genomes were added. Approximately 2500 databases were rebuilt of which approximately 1100 were for HMP (Human Microbiome Project) organisms.

1. Improvements to BioCyc Databases

New Curated Tier 2 Database for Vibrio cholerae O1 El Tor strain N16961

Vibrio cholerae O1 El Tor strain N16961 is a new Tier 2 PGDB for the seventh pandemic O1 El Tor strain N16961. Toxigenic strains of Vibrio cholerae (serogroups O1 and O139), a gram-negative facultative anaerobe, continue to pose a significant threat to human health and safety, evidenced by the ongoing seventh cholera pandemic which began in 1961. This strain was the first fully sequenced V. cholerae genome, and is widely used as a reference strain in studies of the species. This PGDB uses the RefSeq annotation of an updated genome sequence for N16961 (WTSI, 2019), however, gene names and locus tags from the original assembly (Heidelberg et al 2000) have been included.

The PGDB has undergone significant manual curation. This includes the addition of descriptions summarizing the functions of over 300 proteins and RNAs covering key areas of interest such as virulence, biofilm formation, transcriptional regulation, quorum sensing, transporters, secretion systems, cyclic-di-GMP signalling, chemosensory systems, polysaccharide production, toxin-antitoxin systems and small RNAs.

A few examples of curated entries include:

• Major virulence regulators ToxR, ToxS, TcpP, TcpH, and ToxT
• The toxin-coregulated pilus
• The cholera toxin and the RTX toxin type I secretion system
• Heme-containing nitric oxide sensor protein HnoX
• Small RNAs such as the dual function sRNA VcdRP, the Qrr SRNAs, and competence regulator TfoR

2. Improvements to MetaCyc

MetaCyc now contains 3,063 metabolic pathways.

The MetaCyc data were curated from 73,000 publications.

New and Updated Pathways

We have added 56 new pathways to MetaCyc since the last release and revised 16 pathways by modifying pathway diagrams, adding commentary, or updating enzyme and gene information. We also added one superpathway, for a total of 73 new and updated pathways.

The new updated pathways included pathways for bacterial degradation, prokaryotic biosynthesis, antibiotic and toxin biosynthesis, cell components biosynthesis, icosanoids biosynthesis, and photorespiration.

During this quarter we have updated the Enzyme Commission (EC) definitions in MetaCyc with the latest information (as of July 2022) from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) and the Joint Commission on Biochemical Nomenclature (JCBN), available from the ExplorEnz database. MetaCyc now contains 6662 EC numbers (including internal M numbers).

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

3. Improvements to EcoCyc

Highlights of EcoCyc Database Improvements

• We have updated curation of a formerly uncharacterized protein and functional RNA, respectively:
  • SmrB, based on a report by Saito et al who have shown that it is a ribosome rescue factor which cleaves mRNAs upstream of stalled ribosomes and triggers tmRNA-mediated ribosome rescue.

  • Raina et al have characterized the dual-function RNA, AzuCR, which is implicated in the modulation of carbon utilization. AzuCR acts as a base-pairing regulatory RNA and encodes the 28 amino acid small membrane protein, AzuC.

• We have added:
  • A new transport reaction for the divalent metal ion transporter ZupT based on recent characterization of its asymmetric binuclear metal center by Roberts et al.

  • The consensus sequences of 125 transcription factors, which were determined in Baumgart et al. We also added to the database the first regulatory interactions for the transcription factors YieP, YeiE, and YafC, which were determined by Gao et al.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 26.0

Released on April 13, 2022.

Version 26.0 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 26.0 of BioCyc contains 20,005 Pathway/Genome Databases.

Chrome and Firefox are the recommended web browsers for BioCyc, followed by Safari and Edge. Web browsers are incompatible, they can treat the same web page differently.

1. Improvements to BioCyc Databases

• 1823 BioCyc databases were regenerated from the newest RefSeq annotations and the newest version of MetaCyc.
• 510 new databases were added to BioCyc

Brucella ovis ATCC 25840 Upgraded to Tier 2 BioCyc database

This α-proteobacterium is a highly contagious veterinary pathogen causing genetic diseases such as epididymitis, in sheep, resulting in significant economic impacts on the sheep industry worldwide. However, it is non-zoonotic, unlike most other Brucella species, such as B. abortus, B. suis and B. melitensis.

This strain of B. ovis contains many pseudogenes and lacks many of the metabolic traits found in other Brucella species, which are thought to contribute to the restricted host range of B. ovis. However, even though some traits are not characteristic of B. ovis, such as erythritol degradation and urea hydrolysis, many of the genes for these traits are present and have been curated. The B. ovis database update included information from more than 75 publications and resulted in the addition of 84 reactions, 15 transport reactions, 64 complexes, and 1043 Gene Ontology (GO) terms. Additionally, when our curated database for B. abortus 2308 contained a curated summary for a protein with an ortholog in B. ovis, that summary was imported from the B. abortus database into the B. ovis database.

Some example entries include:

• urease 1 subunit A, ureA1
• pyruvate, phosphate dikinase, ppdK
• outer membrane proteins, such as type II toxin-antitoxin system Omp31
• Phd/YefM family antitoxin in chromosome II 26.5 kb composite transposon genomic island
• carbonic anhydrase 1
• erythritol degradation pathway
• LPS core oligosaccharide glucosyltransferase, wadA
• flagellar motor switch protein, fliN

Updates to four BioCyc Cyanobacteria Databases

• Synechococcus elongatus PCC 7942 - During the update we revised 67 proteins to reflect new information that has been published since our last update.
• Synechococcus sp. WH8102 - 20 new publications provided significant updates for 79 proteins, including several transporter proteins, carboxysome shell proteins, nitrogen utilization and regulation proteins, as well as creating the phycobilisome structure that highlights the different core, rod and linker proteins.
• Prochlorococcus marinus pastoris CCMP1986 (MED4) – information from 10 additional publications were added, including updates to the partial TCA cycle (e.g. NADP-dependent isocitrate dehydrogenase, icd) and light harvesting proteins (e.g. PcbA, chlorophyll a/b-binding protein) along with some minor corrections.
• Prochlorococcus marinus marinus CCMP1375 (SS120) – improvement to the organism summary and updates to various nitrogen utilization-associated proteins, such as the nitrogen regulatory protein PII (glnK) and ammonia permease (amtB), were included from 11 publications.

Updates to MetaCyc Version 26.0

MetaCyc now contains 3,006 metabolic pathways from all domains of life. MetaCyc contains the equivalent of 10,079 textbook-pages of mini-review summaries.

New and Updated Pathways

We have added 26 new pathways to MetaCyc since the last release and revised 38 pathways by modifying pathway diagrams, adding commentary, or updating enzyme and gene information. We also updated one superpathway, for a total of 65 new and updated pathways.

Pentose sugar degradation in MetaCyc

Pentose sugars, including D-xylose, L-arabinose, and D-arabinose, are metabolized through three main types of pathways. The first type, common in bacteria, uses isomerases, kinases, and epimerases to yield xylulose 5-phosphate, which feeds into the pentose phosphate pathway. In the second type of pathway, which involves reductases and dehydrogenases and is found mainly in yeast and fungi, pentoses are converted into a sugar alcohol, which is then converted to ribulose 5-phosphate or xylulose 5-phosphate, again feeding into the pentose phosphate pathway. The third type is partially analogous to the archaeal non-phosphorylative Entner-Doudoroff pathway variant, and has been sub-classified into three routes. We have expanded our coverage to include all possible pathways and revised our summaries to provide a more comprehensive background.

• D-arabinose degradation I
• D-arabinose degradation II
• D-arabinose degradation III
• D-arabinose degradation IV
• D-arabinose degradation V
• D-xylose degradation I
• D-xylose degradation III
• D-xylose degradation IV
• D-xylose degradation V
• D-xylose degradation VI
• L-arabinose degradation I
• L-arabinose degradation II
• L-arabinose degradation III
• L-arabinose degradation IV
• L-arabinose degradation V

Glucosinolate biosynthesis in MetaCyc

The glucosinolates are secondary metabolites found in 16 plant families, including agriculturally important crop plants of the Brassicaceae such as cabbage, mustard, oilseed rape, and broccoli, as well as the model plant Arabidopsis thaliana, and are responsible for the typical sharp taste and odor of these plants. The configuration of the double bond in the glucosinolate structure has been controversial - some publications report it to be (Z) while others claim it is (E). As a result, the structures in MetaCyc have been inconsistent. We have recently confirmed with experts in the field that all glucosinolates have a (Z) configuration, and have updated all structures and pathways accordingly.

• glucosinolate activation
• aromatic glucosinolate activation
• indole glucosinolate activation (intact plant cell)
• glucosinolate biosynthesis from dihomomethionine
• glucosinolate biosynthesis from hexahomomethionine
• glucosinolate biosynthesis from homomethionine
• glucosinolate biosynthesis from pentahomomethionine
• glucosinolate biosynthesis from phenylalanine
• glucosinolate biosynthesis from tetrahomomethionine
• glucosinolate biosynthesis from trihomomethionine
• glucosinolate biosynthesis from tryptophan
• glucosinolate biosynthesis from tyrosine

Biosynthesis of compounds of pharmacological importance in MetaCyc

We have curated several pathways for the biosynthesis of secondary metabolites of pharmacological importance.

• ansamitocin P biosynthesis
• atranorin biosynthesis
• grayanate biosynthesis
• isoorientin biosynthesis II
• leinamycin biosynthesis
• malbrancheamide biosynthesis
• tropane alkaloids biosynthesis
• valinomycin biosynthesis

Other MetaCyc biosynthetic pathways

• (3R)-N-[(2S)-1-hydroxy-6-[(3R)-3-isocyanobutanamido]hexan-2-yl]-3-isocyanobutanamide biosynthesis
• brassinolide biosynthesis II
• calystegine biosynthesis
• coenzyme A biosynthesis III (archaea)
• mycobactin biosynthesis
• N¹-methyl-N³-aminocarboxypropyl-pseudouridine-modified rRNA biosynthesis
• NiFe(CO)(CN)₂ cofactor biosynthesis
• plasmalogen biosynthesis II (anaerobic)
• salicylate biosynthesis II

MetaCyc degradation pathways

D-tagatose is the C-4 epimer of D-fructose. It is a low-calorie natural sugar present in small amounts in fruits and milk products, and can replace sucrose in food. Its low glycemic index and antihyperglycemic effect make D-tagatose a promising sweetener. We added a pathway for its degradation. L-carnitine is a zwitterionic quaternary amine carboxylate that has essential and diverse roles in intermediary metabolism in all living kingdoms, and γ-butyrobetaine is a metabolite involved in the biosynthesis and degradation of L-carnitine. We updated two of the L-carnitine degradation pathways, and expanded our coverage of γ-butyrobetaine degradation from one to three pathways. Glycine betaine is a very efficient osmolyte found in a wide range of bacteria and plants, where it accumulates at high cytoplasmic concentrations in response to osmotic stress to act as an osmoprotectant. We have added a new glycine betaine degradation pathway and revised an existing one. We have also updated pathways for syringate and toluene degradation to reflect new knowledge.

• D-tagatose degradation
• γ-butyrobetaine degradation I
• γ-butyrobetaine degradation II
• γ-butyrobetaine degradation III
• glycine betaine degradation I
• glycine betaine degradation III
• L-carnitine degradation I
• L-carnitine degradation III
• syringate degradation
• toluene degradation to benzoyl-CoA (anaerobic)

Protein glycosylation in yeast added to MetaCyc

Protein O-mannosylation is an essential protein modification in fungi and animals. In the yeast Saccharomyces cerevisiae mannosyl O-glycans are short oligomannose chains that are attached via a glycosidic bond in α anomeric configuration to the hydroxyl group of Ser or Thr residues. We updated the pathway describing this modification. N-linked glycosylation is an important protein modification in which oligosaccharides are attached to an Asn residue. This type of glycosylation is found in eukaryotes and archaea, and very rarely in bacteria. The pathway leading to the biosynthesis of a tetradecasaccharide precursor is highly conserved, but later processing and elongation steps differ among different organisms. We have added two new pathways that describe late stages of N-glycosylation in yeast. One pathway applies to proteins targeted for retention in cellular organelles, while the other applies to proteins that are destined to the cell wall and to some periplasmic proteins.

• protein N-glycosylation processing of mannoproteins (cis-Golgi, yeast)
• protein N-glycosylation processing of proteins targeted for retention in cellular organelles (cis-Golgi, yeast)
• protein O-mannosylation I (yeast)

Assorted other MetaCyc pathways

EC 6.2.1.1, acetate—CoA ligase, usually converts acetate to acetyl-CoA at the expense of ATP. However, in the bacterium Syntrophus aciditrophicus high diphosphate levels and a high AMP-to-ATP ratio support the operation of the enzyme in the acetate-forming direction, generating ATP. The GABA shunt II pathway describes a route that allows the cyanobacterium Synechocystis sp. PCC 6803 to convert 2-oxoglutarate to succinate, closing an otherwise incomplete TCA cycle. We also updated the pyruvate fermentation to acetate V pathway, which was previously known to occur only in trypanosomatids and some parasitic helminths, to reflect the recent discovery of the pathway in a bacterium.

• acetate and ATP formation from acetyl-CoA III
• GABA shunt II
• pyruvate fermentation to acetate V

Other Improvements

Update of EC Reactions:

During this quarter we have updated the Enzyme Commission (EC) definitions in MetaCyc with the latest information (as of February 2022) from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) and the Joint Commission on Biochemical Nomenclature (JCBN), available from the ExplorEnz database. MetaCyc now contains 6621 EC numbers (including internal M numbers).

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

Updates to EcoCyc Version 26.0

The EcoCyc data have been curated from 42,148 publications. It includes the equivalent of 3775 textbook-pages of mini-review summaries.

EcoCyc Modeling Tab Contains Predictions from E. coli Whole Cell Model

This version of EcoCyc contains predictions from computer simulations of an E. coli cell from the E. coli whole-cell modeling project. The aim of the project is to build a computational representation of an E. coli cell that fully captures the dynamics of every known molecule within an E. coli cell, using a heterogeneous set of parameters that are curated from decades of research conducted on this model microbe. The model ties together multiple submodels that each represent a particular domain of an E. coli cell, using the mathematical framework that is most appropriate for the given domain. Macklin et al., 2020 provides more details on how the model was constructed and how its outputs were validated.

The predictions are present on the new Modeling tab on EcoCyc gene pages (example). The Modeling tab contains predictions of the cellular copy numbers for the mRNA and protein product of that gene under three conditions of E. coli growth: aerobic and anaerobic growth under M9 medium with 0.4% glucose, and aerobic growth under M9-derived rich medium. The presented data were calculated by running a batch of computer simulations of an E. coli cell.

Through a collaborative effort between the EcoCyc team and the whole-cell modeling project team at Stanford, we have built a pipeline that allows the whole-cell model to import a subset of the required input parameters, which includes genome annotations, RNA/protein sequences, metabolic reaction networks, transcription factor networks, and reaction stoichiometries, directly from the latest release of the EcoCyc database. With each updated release of EcoCyc, a new batch of simulations is initialized with the newly imported parameters from EcoCyc, and the outputs from the updated simulations are reported on the modeling tabs for EcoCyc gene pages.

The whole-cell model simulates the dynamics of individual cells, which allows it to capture how stochastic processes can lead to heterogeneity between cells that are grown under the same conditions. Thus, in addition to the mean values that are taken from the average of all simulated cells, we are also able to report the standard deviations of each value between the simulated cells, which are presented as error terms in the provided data.

The latest released version of the model code can be accessed for a closer look into the inner workings of the whole-cell model. Please note that the Modeling tab data were generated from the latest working version of the model that contains further updates that may lead to output values that are different from the released version.

Highlights of EcoCyc Database Improvements

• We have expanded the corpus of E. coli literature available for searching within EcoCyc to 48,189 abstracts plus 38,269 full-text articles (see Tools → Search → Search Full Text Articles).

• We have added one new pathway: NiFe(CO)(CN)₂ cofactor biosynthesis
• Sellner et al. and Junkermeier et al. have described the production of a novel surface-associated polysaccharide that is exploited as a phage receptor in both pathogenic and non-pathogenic E. coli. The inner membrane cyclic di-3',5'-guanylate-activated glycosyltransferase NfrB, the outer membrane protein NfrA, and a periplasmic protein YbcH are all implicated as components of a secretion system responsible for biosynthesis and export of the uncharacterized sugar.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

2. New in the BioCyc Website

• Most graphics within Pathway Tools generated web pages can now be printed to a PDF file by clicking the printer icon that appears to the left when you mouse over the graphic. Examples of printable graphics include genome-browser images, pathway diagrams, complete metabolic network diagrams, and the regulation summary diagrams that appear in gene pages.
• Large pathway diagrams are now scaled to fit within the web browser page; they can be zoomed by moving your mouse into the pathway diagram and moving the mouse wheel or using the zoom controls that appear on the left.
• A number of improvements have been made to comparative analysis operations. For example, they have been extended to support the (relatively) new EC 7 enzyme class.

Release Notes for BioCyc Version 25.5

Released on December 15, 2021.

Version 25.5 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 25.5 of BioCyc contains 19493 Pathway/Genome Databases.

Chrome and Firefox are the recommended web browsers for BioCyc, followed by Safari and Edge. Web browsers are incompatible, they can treat the same web page differently.

1. Improvements to BioCyc Databases

• New databases for two model organisms were added. These include:
  • Rattus norvegicus This is a Tier 3 (uncurated) database built from the BN7.2 assembly and includes links (for genes) to the Rat Genome Database.
  • Caenorhabditis elegans This is a Tier 3 (uncurated) database and includes links (for genes) to Wormbase.

New Curated Tier 2 PGDB for Helicobacter pylori 26695

Helicobacter pylori is a Gram-negative bacterium that is often found in the human stomach. It is helix-shaped (giving the genus its name), presumably to help it penetrate the mucoid lining of the stomach and reach the epithelial cells underneath, where it escapes the acidic environment of the stomach.

H. pylori infections are common and usually have no symptoms. In 2015 it was estimated that more than 50% of the world's population is colonized by the bacterium. However, in 10-20% of the cases an infection results in gastritis (stomach inflammation) or ulcers. In some cases the infection may lead to the development of certain cancers. Pathogenicity is correlated with the presence of pathogenicity islands in the genome, though disease outcome depends on additional factors, such as the host's physiology, genotype and dietary habits.

For this release we generated a completely new PGDB for H. pylori 26695, based on the latest available RefSeq annotation. The database underwent significant curation, incorporating data from over 900 publications. Important curated topics include lipopolysaccharide biosynthesis, flagellum biosynthesis, 4 different secretion systems, restriction modification systems, large protein and RNA complexes, and much more. An emphasis was placed on metabolism directly involved in pathogenicity. New pathways were generated to describe the aerobic and anaerobic respiration of the organism, and the biosynthesis of its unique lipopolysaccharides, which contains Lewis (Le) antigens, structures typically found on human epithelial and cancer cells, that allow the organism to evade innate and adaptive immune responses.

A few example entries include:

• Cag type IV secretion system
• Flagellar motor switch protein FliG
• Urease
• NiFe(CO)(CN)₂ cofactor biosynthesis
• Nickel response regulator NikR
• Type I restriction-modification system HpyAXIII
• RecA recombinase
• Methyl-accepting chemotaxis protein TlpB
• Ferredoxin-menaquinone dehydrogenase

Lactococcus lactis subsp. lactis IL1403 This PGDB has received significant curation upgrades since its initial release at the tier 2 level. Curation from more than 50 additional peer-reviewed publications have resulted in 12 new reactions, 22 imported reactions, 3 new pathways, 81 new and corrected gene names, and 117 summaries for genes, proteins and transporters. Some highlights of the enzymes, reactions and pathways that we have curated:

• Fermentation metabolic enzymes and pathways, such as the lactate dehydrogenase enzyme, and various alternative NAD+ regeneration pathways, including the 2,3-butanediol and mannitol biosynthesis pathways
• Fifteen transporters including PTS systems responsible for the uptake of sugars, ABC family transporters that mediate uptake of various peptides, amino acids and osmoprotectants, and several multidrug efflux transporters
• Enzymes and reactions of peptidoglycan metabolism, cell wall polysaccharide production, and menaquinone biosynthesis
• Enzymes involved in proton motive force (PMF)-generation via electron transport chain that functions when L. lactis is grown aerobically

BsubCyc upgrades The BsubCyc PGDB currently contains references to 197 papers published in 2021.
New curation includes:

• Addition of experimental evidence codes to 16 gene products
• Addition of one new metabolic pathway, S-(2-succinyl)-L-cysteine degradation

Updates to MetaCyc Version 25.5

MetaCyc now contains 2980 metabolic pathways from all domains of life. MetaCyc contains the equivalent of 10757 textbook-pages of mini-review summaries.

We have added 11 new pathways to MetaCyc since the last release.

Some highlights of the new additions to MetaCyc include:

Degradation Pathways

The TCA cycle intermediate fumarate can react spontaneously with thiol-containing nucleophiles such as cysteine and glutathione to form S-(2-succinyl)-adducts. A new pathway described from Bacillus subtilis enables the organism to detoxify these compounds and use them as a sulfur source.

• S-(2-succinyl)-L-cysteine degradation

Inulin is a type of fructan - a polysaccharide composed of D-fructose chains attached to a terminal glucose. The fructose units in inulins are joined by a β(2→1) glycosidic bond. This new pathway describes the degradation of inulin via difructose anhydride III (DFA III), a low-calories sugar substitute with commercial potential.

• inulin degradation

Fucose is a common sugar, found in N-linked glycans on mammalian, insect and plant cell surfaces, in many bacterial glycans, and in other biomolecules. It has been shown to be metabolized via two pathway variants, one leading to formation of (S)-lactaldehyde, while the other forms pyruvate and (S)-lactate. We have now added the second variant, which was originally described from pig liver, and has been characterized in detail from several bacterial species.

• L-fucose degradation II

Biosynthetic Pathways

Cyclobis-(1→6)-α-nigerosyl, also known as cycloalternan, is a cyclic glucotetraose with alternate α(1→6)- and α(1→3)-glucosidic linkages, produced by several bacterial species during the degradation of complex glycans. The compound is formed extracellularly, and is degraded after its import into the cell.

• cyclobis-(1→6)-α-nigerosyl biosynthesis

Other Improvements

Update of EC Reactions:

During this quarter we have updated the Enzyme Commission (EC) definitions in MetaCyc with the latest information (as of October 2021) from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) and the Joint Commission on Biochemical Nomenclature (JCBN), available from the ExplorEnz database. MetaCyc now contains 6560 EC numbers (including internal M numbers).

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

Updates to EcoCyc Version 25.5

The EcoCyc data have been curated from 41,490 publications. It includes the equivalent of 3751 textbook-pages of mini-review summaries. Significant updates to EcoCyc include:

• Enzyme I (EI) of the bacterial phosphotransferase system is known to form clusters that localize to the cell poles. Szoke et al. now report that EI is recruited to the poles by a formerly uncharacterized protein, TmaR. Polar localization of both proteins is dependent on tyrosine phosphorylation and TmaR-mediated polar sequestration, and release of EI serves to regulate sugar metabolism.

• We added new conformations for some transcription factors, including dimers for the transcriptions factors FrlR (Graf von Armansperg et al.) and DgoR (Arya et al.) as well as the new inactive conformations FrlR-fructoselysine-6-phosphate (Graf von Armansperg et al.) and MprA-salicylate (Arshad et al.).

• Summaries for four sigma factors and 29 transcription factors were updated.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 25.1

Released on August 5, 2021.

Version 25.1 is a minor release that includes updates to the BioCyc website and downloadable data files.

Version 25.1 of BioCyc contains 19,535 Pathway/Genome Databases. A total of 1,750 new genomes were added, of which 1710 are for NCBI reference/representative genomes.

1. Improvements to BioCyc Databases

Brucella abortus 2308 Upgraded to Curated Tier 2 Database

This Gram-negative Α-proteobacterium is the causative agent of brucellosis in cattle, resulting in infertility and abortions and significant economic impacts worldwide. It is also a serious zoonotic disease for humans in close contact with or drinking raw milk from infected animals. Brucella abortus is a facultative intracellular pathogen that infects phagocytic cells of the immune system, effectively evading detection. This upgrade has focused on curation of proteins, reactions and metabolic pathways associated with the virulence and immune evasion mechanisms of Brucella abortus 2308. These include O-antigen biosynthesis proteins, a Type IV secretion system (new to BioCyc) with more than a dozen putative T4SS substrates and effector proteins, and more than 50 small RNAs. Additional database upgrades include:

• Rerunning the enzymatic reaction and pathway prediction algorithms, resulting in an increase of >50 enzymatic reactions and 13 pathways to a total of 571 and 83, respectively
• Creation of 39 new protein complexes and 10 new transporters
• Literature-based summaries for 285 proteins from >70 peer-reviewed publications.

2. Improvements to MetaCyc

We have added 32 new pathways to MetaCyc since the last release and revised 17 pathways by modifying pathway diagrams, adding commentary, or updating enzyme and gene information. We also updated two superpathways, for a total of 51 new and updated pathways. The new pathways fall under the following categories:

• Central Metabolism Pathways (2 new pathways)
• Degradation Pathways (8 new pathways)
• Biosynthetic Pathways (5 new pathways)
• Lipid A Biosynthesis (4 new pathways)
• Secondary Metabolism Pathways (7 new pathways)
• Archaeal Metabolism (2 new pathways)
• Eukaryotic Pathways (1 new pathway)
• Phage Pathways (1 new pathway)

Update of EC Classification

During this quarter we have updated the Enzyme Commission (EC) definitions in MetaCyc with the latest information (as of July 2021) from the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) and the Joint Commission on Biochemical Nomenclature (JCBN), available from the ExplorEnz database. MetaCyc now contains 6563 EC numbers (including internal M numbers).

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

3. Improvements to EcoCyc

EcoCyc includes the following updates:

We have added two new pathways:

• L-aspartate degradation II (aerobic)
• L-aspartate degradation III (anaerobic)

Three existing metabolic pathways were modified based on new information in the literature:

• N-acetylneuraminate and N-acetylmannosamine degradation I
• uracil degradation III
• chitobiose degradation

The summaries for 29 transcription factors and 6 sigma factors were updated.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 25.0

Released on May 20, 2021.

Version 25.0 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 25.0 of BioCyc contains 17,835 Pathway/Genome Databases.

Chrome and Firefox are the recommended web browsers for BioCyc, followed by Safari and Edge. Web browsers are incompatible, they can treat the same web page differently.
If you are having difficulties with the new BioCyc release, try doing a hard reload (hold down the Shift key and click the Reload button on your browser); deleting cookies can also help.

1. Improvements to BioCyc Databases

Updates to BioCyc Databases

• 2427 BioCyc databases were regenerated from the newest RefSeq annotations and the newest version of MetaCyc.
• Updates to Chlamydia trachomatis D/UW-3/CX include improvement of the central metabolic pathways, additional curation of lipoate metabolic genes, protein complexes and reactions, and additional representations of transporters and their reactions.
• Acinetobacter baumannii AB5075-UW was upgraded from a Tier 3 to a tier 2 PGDB primarily through propagation of orthologous genes from the closely related Acinetobacter baumannii ATCC 17978 PGDB. Both PGDBs were updated further through curation of genes associated with the GacSA two-component regulatory system and the phenylacetate degradation genes, transcriptional unit and pathway, as well as the type II secretion system.
• BsubCyc upgrades: For this release, we have curated 151 gene products that encode transmembrane transporters or transporter components. Curation included the creation of 14 new transporter protein complexes. 17 additional, not transport-related proteins were fully curated. BsubCyc currently contains references to 223 papers published in 2020 and 58 papers published in 2021.
  • We have added a new signal transduction pathway for the PsdSR two-component signal transduction system.

Updates to MetaCyc Version 25.0

MetaCyc now contains 2937 metabolic pathways from all domains of life. MetaCyc contains the equivalent of 9739 textbook-pages of mini-review summaries.

We have added 85 new pathways to MetaCyc since the last release and revised 15 pathways by modifying pathway diagrams, adding commentary, or updating enzyme and gene information. We also added two superpathways, for a total of 102 new and updated pathways.

Some highlights of the new additions to MetaCyc include:

Lipopolysaccharide biosynthesis

The lipopolysaccharides (LPS) are composed of three components – lipid A, the core oligosaccharide, and the O antigen. We have added several pathways that describe the biosynthesis of lipid A and the core oligosaccharides of Brucella species and Porphyromonas gingivalis, and added many pathways for the biosynthesis of O antigens. We now have full coverage of the O antigens produced by Salmonella species, by many Escherichia coli serotypes, and by Brucella abortus, Porphyromonas gingivalis, and some strains of Shigella boydii.

Other Polysaccharide-Related Biosynthetic Pathways

We created a new pathway for the biosynthesis of colanic acid, an exopolysaccharide secreted by E. coli and a number of other Enterobacteriaceae. We also revised existing pathways for the biosynthesis of succinoglycan and the enterobacterial common antigen (ECA).

Arsenic Metabolism

Arsenic is a natural component of the earth’s crust and is widely distributed throughout the environment in the air, water and land. It exists most commonly in the (III) and (V) oxidation states, and many compounds of both forms are highly toxic. All organisms have developed defense mechanisms to cope with arsenic compounds. In this release we performed an extensive revision of our coverage of arsenic compound metabolism. We now have an up-to-date coverage of all known arsenic-related enzymes in bacteria, yeast, plants and animals.

Electron Transport in Cyanobacteria

EC 7.1.1.10, ferredoxin—quinone oxidoreductase (H+-translocating) is a key enzyme in the electron transfer chain of cyanobacteria and plastids that until recently has been mischaracterized. The enzyme couples electron transport from ferredoxin to plastoquinone with proton pumping from the cytoplasm to the thylakoid lumen, and participates in cyclic electron flow, retuning electrons generated by photosystem I to the plastoquinone pool, thus bypassing the generation of reducing power. Based on the new functional characterization of the enzyme we have revised several cyanobacterial electron transport pathways and created a new pathway to describe cyclic electron flow.

11-oxyandrogens

A new pathway describes the biosynthesis of 11-oxygenated C19 steroids (11-oxyandrogens). These steroids have long been recognized as major androgens in teleost fishes. However, more recently it has been discovered that they are also produced in humans and play an important role in several disorders such as congenital adrenal hyperplasia (CAH), polycystic ovary syndrome (PCOS), and premature adrenarche.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

Updates to EcoCyc Version 25.0

The EcoCyc data have been curated from 40,472 publications.

Significant updates to EcoCyc include:

• Enzyme I (EI) of the bacterial phosphotransferase system is known to form clusters that localize to the cell poles. Szoke et al. now report that EI is recruited to the poles by a formerly uncharacterized protein, TmaR. Polar localization of both proteins is dependent on tyrosine phosphorylation and TmaR-mediated polar sequestration, and release of EI serves to regulate sugar metabolism.

• We added new conformations for some transcription factors, including dimers for the transcriptions factors FrlR (Graf von Armansperg et al.) and DgoR (Arya et al.) as well as the new inactive conformations FrlR-fructoselysine-6-phosphate (Graf von Armansperg et al.) and MprA-salicylate (Arshad et al.).

• Summaries for four sigma factors and 29 transcription factors were updated.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

2. New in the BioCyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Website Design Refresh: We have updated the BioCyc website to give it a more modern look and to increase its accessibility to new users.

• Multi-PGDB Searches: Several of the searches available under Tools → Search now enable searches across multiple organism databases (up to 70). For example, this option enables searching across multiple strains or members of a microbial community to find which organisms contain a given gene, metabolite, or pathway. All the search and filtering options applicable to that search are supported. The searches include
  • Search Genes, Protein or RNA
  • Search Compounds
  • Search Reactions
  • Search Pathways

• Multiple Sequence Alignment: The alignment tool at Tools → Analysis → Multiple Sequence Alignment now supports alignment of arbitrary nucleotide regions of a replicon, and aligning user-provided sequences in addition to sequences from BioCyc databases.

• Comparative Analysis: Many improvements have been made to the comparative tools under Tools → Analysis → Comparative Analysis:
  • The tools are significantly faster.
  • The organism comparison provides new comparisons of phenotype metadata, collection metadata, and annotation metadata
  • The reactions comparison now identifies both shared and unique reactions between organisms
  • Comparisons of biosynthetic pathways now provide both a pathway view and a metabolite view that more clearly identifies which metabolites can be synthesized -- see example
  • The compounds comparison now identifies both shared and unique metabolites between organisms

Release Notes for BioCyc Version 24.5

Released on January 7, 2021.

Version 24.5 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 24.5 of BioCyc contains 18,030 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

Updates to Other databases

• 1654 databases were regenerated from the newest RefSeq annotations and the newest version of MetaCyc. No new databases were added in this release.
• BsubCyc upgrades: BsubCyc has added references to new publications to 130 genes. Nine of these genes were also renamed in the cited publications. BsubCyc cites 197 papers published in 2020 and 233 published in 2019. GO terms with experimental evidence were added to 44 gene products, for a total of 797 gene products annotated with experimental GO terms.

Chlamydia trachomatis D/UW-3/CX Upgraded to Tier 2 Curated Database

This reference genome is the first Chlamydia genome in the BioCyc database to be upgraded from Tier 3 to Tier 2. Chlamydia trachomatis, originally named Rickettsia trachomae, are obligate intracellular bacterial pathogens that grow in membrane bound vacuoles within the cytoplasm of their eukaryotic host cells. The strain D/UW-3/CX belongs to serovar D, which is associated with sexually transmitted infections in humans and is the common causative agent of urogenital tract pathologies that can lead to infertility and increased risk of HIV infection. This intracellular pathogen has a reduced genome, is known to utilize host derived carbon/energy sources and is characterized by a unique developmental cycle. This update of Chlamydia trachomatis D/UW-3/CX has focused on curating the proteins and reactions associated with the central metabolic pathways and differential activity associated with distinct phases of the developmental cycle. Database upgrades include:

• Rerunning the enzymatic reaction and pathway prediction algorithms followed by curator review, resulting in an increase of more than 51 enzymatic reactions and 7 pathways to a total of 571 and 83, respectively.
• Creation of 10 new protein complexes
• Literature-based curation from 35 publications, resulting in experimental evidence for 84 additional genes and proteins and significant improvement in the central metabolic pathways.
• 2685 protein features were imported from UniProt

BioCyc contains databases for 127 sequenced Chlamydia genomes, 15 of which are representative or reference genomes.

Updates to MetaCyc Version 24.5

MetaCyc now contains 2,859 metabolic pathways from all domains of life. MetaCyc contains the equivalent of 10,179 textbook-pages of mini-review summaries.

We have added and/or updated 15 pathways in MetaCyc since the last release.

Significant updates to MetaCyc include:

• During this release period we curated pathways for the biosynthesis of seven of the most common O antigens of Salmonella, which are found in members of groups A, B, C2, D1, D2, D3 and E.
• Added a pathway for the generation of 5α-dihydrotestosterone (DHT) that does not involve testosterone.
• Added a pathway for production of cholesterol in red alga (e.g. Chondrus crispus) that differs from that in plants.
• Added a novel dTMP biosynthetic pathway unique to mitochondria.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

Updates to EcoCyc Version 24.5

The EcoCyc data have been curated from 39,932 publications.

Significant updates to EcoCyc include:

• YedR has been characterized as a non-essential cell division protein and renamed to DrpB
• Updated the summaries and regulatory interactions of most small RNAs encoded by E. coli K-12
• Added 675 protein localizations from PSORT and Gravy

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

2. New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Metabolic Network Explorer: The new Metabolic Network Explorer facilitates the interactive exploration of the metabolic network around a set of connected compounds of interest. To access this tool, go to Metabolism → Metabolic Network Explorer and enter a starting metabolite. You can then build up a linear reaction path by adding successive reactions forward or backward from the current path. For each metabolite along the central path, lists of precursor and successor metabolites provide information about other possible connections to that metabolite, and allow the user to extend or change the central path to follow one of those connections. Various customizations are supported.

• Regulatory Overview: We've upgraded the regulatory network browser (Regulatory Overview) to utilize HTML5 canvas graphical rendering via our Webgraphics package, yielding better quality graphics and faster zooming. We also have incorporated changes that enable the user to display successive levels of regulation one level at a time, and to print to a file either the entire regulatory network, or the network regulated by a single gene.

• Circular Genome Viewer: A new circular genome viewer tool provides a global view of the organization of one or more chromosomes as a set of concentric circles (tracks) containing features (genes, promoters, binding-sites, other extragenic sites) of interest. A given track can be customized to show and/or highlight features that match specified criteria. For example, a track can be filtered to only show RNA genes, or transporters, or genes from an uploaded file. Alternatively, a track might show all genes, but highlight those involved in certain pathway classes or annotated to specified GO terms. The circular genome viewer can also be used to compare chromosomes from multiple closely related strains, such that highlights can be applied to orthologs across all strains. See Genome → Circular Genome Viewer.

• Genome Overview: Genome Overview already was using Webgraphics for rendering, but we added the ability to highlight genes, either by the gene name or identifier, or by highlighting those genes whose name has a shared substring.

• Multiple Sequence Alignment: We've updated Multiple Sequence Alignment to utilize Clustal Ω for computing the alignments and to utilize MSAViewer for the visualization of the alignments.

• Comparative Analysis: The organism comparison report now compares organism metadata. The reaction comparison report now includes those reactions unique to each organism.

Release Notes for BioCyc Version 24.1

Released on September 8, 2020.

Version 24.1 is a minor release that includes updates to the BioCyc website and downloadable data files.

Version 24.1 of BioCyc contains 18,023 Pathway/Genome Databases, of which 1,247 are new genomes and 680 of the PGDBs were re-generated. 1,927 of the PGDBs are for NCBI representative genomes.

1. Improvements to BioCyc Databases

Integration of Phenotype Microarray Datasets

We have added Biolog Phenotype Microarray data to the six BioCyc databases listed below. To navigate to the Phenotype Microarray data in BioCyc, click on a link to an organism page below, then, click on the "List" button in the table row for "Phenotype Microarray Datasets".

• Acinetobacter baumannii ATCC 17978
• Acinetobacter baumannii AYE
• Acinetobacter baumannii D1279779
• Acinetobacter baumannii ACICU
• Pectobacterium parmentieri SCC3193
• Pseudoalteromonas haloplanktis AC125

Curation of Acinetobacter baumannii ATCC 17978 Database

This BioCyc database has been upgraded from Tier 3 to Tier 2. Strain ATCC 17978 presented in this PGDB is from a polymyxin B- resistant substrain of the original, 1951 clinical isolate from a fatal infant meningitis, originally named Moraxella glucidolytica nonliquefaciens. This strain carries two plasmids, which contain some predicted virulence factors, including TonB-dependent receptors. Strain ATCC 17978 is one of the well-studied, multidrug-resistant, pathogenic strains that is responsible for a range of community- and hospital-acquired infections and has been included among the World Health Organizations list of pathogens of major public health concern. For this updated database, we have focused on virulence factors such as those related to metal acquisition systems and outer membrane proteins. Database updates include:

• Rerunning the pathway prediction algorithm followed by curator review, resulting in an increase of more than 40 pathways to a total of 253.
• Literature-based curation from more than 80 publications, resulting in experimental evidence for 178 additional genes and proteins and significant improvement in the corresponding enzymatic and transport reactions.
• The number of protein complexes and transporters increased by 38 and 25, respectively.
• 4450 protein features were imported from UniProt
• A Phenotype Microarray dataset was imported

BioCyc contains databases for 265 sequenced Acinetobacter genomes.

Updates to Lactobacillus rhamnosus GG Database

We further refined the Tier 2 PGDB for this organism by performing the following:

• Propagation of cumulative changes in MetaCyc to synchronize the two databases.
• Removal of incorrectly predicted enzymatic reaction, transport activities, and metabolic pathways.
• Addition of 12 new pathways: exopolysaccharide biosynthesis, NADH to cytochrome d electron transfer, NADP biosynthesis, polyphosphate metabolism, bile acids deconjugation, 2-deoxy-D-glucose 6-phosphate degradation, arsenate detoxification III (thioredoxin), alanine racemization, 2-deoxy-D-ribose degradation I, 5-oxo-L-proline metabolism, tRNA-uridine 2-thiolation and selenation, and lipoprotein posttranslational modification.
• Creation of more protein complexes (the number of protein complexes increased from 37 to 85, including large complexes such as the ribosome).
• Literature-based curation of PubMed publications that include specific metabolic information about the organism. Among the newly curated proteins are alpha-L-fucosidases A, B and C; all enzymes involved in biosynthesis of the main exopolysaccharide (WelEFGHIJ); the proteins that make up the SpaCBA and spaFED pili and their sortases; mucus-binding factor (Mbf); adhesin (MabA); lectin-like proteins 1 and 2 (Llp1 and Llp2); major secreted proteins 1 and 2 (Msp1 and Msp2, also known as P75 and P40); NADH oxidase; lactate dehydrogenases LdhD1 and LdhD2; glutamate dehydrogenase GdhA; glutathione peroxidase Gpx; glutathione reductase GshR; glutathione ABC transporter; L-fucose/H+ symporter FucP; fucose isomerase FucI; and bacteriocin.

Updates to MetaCyc Version 24.1

MetaCyc now contains 2,847 metabolic pathways -- we have added or significantly revised 39 pathways in this release.

MetaCyc contains the equivalent of 10,111 textbook-pages of mini-review summaries.

Areas of MetaCyc curation for this release include new pathways in the following areas:

• Fatty acid metabolism
• Stickland reactions
• Cofactor biosynthesis
• Sulfur compound metabolism
• Biosynthetic bacterial pathways
• Cyanobacterial pathways
• Plant pathways
• Fungal pathways

Database links for proteins in MetaCyc have been updated. Previously there were four database names associated with links to ENTREZ ids in MetaCyc: PID, REFSEQ, NCBI-REFSEQ-PRO, and GI. All of these links used ENTREZ identifiers and all are now linked using the database name PID.

MetaCyc Sequence Files: The sequence files used by the PathoLogic pathway hole-filler have been enhanced to include ids and sequences from ENTREZ in addition to UniProt. These files identify proteins in UniProt and ENTREZ that are associated with different enzyme activities. These files were previously called uniprot-seq-ids.dat and uniprot-seq-ids.seq. The new files, which are available in the MetaCyc flat-file distribution, are now called the following. All of the files are formatted as Lisp lists, actually as a list of lists. Each Lisp list is a series of items enclosed in parentheses.

• protein-seq-ids-reduced-70.dat -- A list of lists, where each list contains a MetaCyc reaction id, an EC number, and one or more protein identifiers with a prefix of either UNIPROT for uniprot identifiers or PID for ENTREZ-derived identifiers. In this file, sequences with more than 70% blast similarity to previously processed sequences have been removed as "redundant." The .seq file is supplied for the reduced set only.

• protein-seq-ids-reduced-70.seq -- A list of lists, with each list consisting of a protein id with database prefix, followed by the amino acid sequence of the protein specified by the id. Corresponds to the preceding .dat file.

• protein-seq-ids-unreduced.dat -- Similar to protein-seq-ids-reduced-70.dat, but no removal of similar sequences has been performed.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

Updates to Other E. coli PGDBs in BioCyc 24.1

To improve the other E. coli PGDBs in BioCyc (meaning those PGDBs describing strains other than K-12 MG1655), we propagated gene and protein annotations from EcoCyc to the 480 other E. coli PGDBs in BioCyc. On average, each of those PGDBs received updates to 2535 gene or proteins. The information we propagated included gene and protein names, protein complex assignments, and the reactions assigned to each protein. Propagation was performed from a gene or protein in EcoCyc only if it had experimental support, and only if the existing annotations for the target gene or protein did not have experimental evidence. The target gene/protein is a computed ortholog of the source gene/protein. The propagation event was recorded in a "history entry" for the target gene/protein that is displayed on the gene/protein page and explains what information was propagated.

Updates to EcoCyc Version 24.1

The EcoCyc data have been curated from 39,000 publications.

• New functions were added to the membrane proteins YihG, characterized as a lysophosphatidic acid acyltransferase which affects swimming motility, and DigH (formerly YddW), a glycosyl hydrolase that cleaves denuded peptidoglycan during cell division.

• Bradley et al. have reported that YcaQ is an alkylpurine DNA glycosylase involved in the repair of interstrand DNA crosslinks.

• Kentache et al. and Bell et al. (and references therein) have elucidated the function of NanY in E. coli. The enzyme is involved in the utilization of dehydrated forms of N-acetylneuraminate as a source of carbon and energy. The gut bacterium Ruminococcus gnavus is able to convert host-derived mucins to 2,7-anhydro-α-N-acetylneuraminate, which appears to be imported and utilized by E. coli.

• A total of 1009 new regulatory interactions from high throughput experiments have been uploaded for the following transcription factors:
  • ArcA from Federowicz et al.
  • ArgR from Caldara et al. and Cho et al.
  • CsiR from Aquino et al.
  • FNR from Federowicz et al.
  • Lrp from Cho et al. and Kroner et al.
  • Nac from Aquino et al.
  • OmpR from Shimada et al.

• Promoters were modified to be consistent with the definition in Mejia-Almonte et al.. When RNA polymerase initiates transcription using a different sigma factor, even if using the same transcription start site (TSS), we now consider it a different promoter. As a consequence, we generated new promoters (and consequently new transcription units), each with a different sigma factor, that share the same TSS.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 24.0

Released on May 14, 2020.

Version 24.0 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 24.0 of BioCyc contains 16,817 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

• ~120 new databases are included in this release, mostly for NCBI reference genomes. To find the reference genomes, click "change organism database" at the top-right of the BioCyc home page, then click the "Organism Filter" menu in the upper right of the pop-up window.

• ~2,000 databases were regenerated from the newest RefSeq annotations and the newest version of MetaCyc

• A number of duplicate or low-quality databases were removed

• Mycobacterium tuberculosis H37Rv
  • A curation update was performed to include new gene functions and pathways from recent publications

• BioCyc contains three new, highly curated cyanobacterial Pathway/Genome Databases, in addition to one previously existing curated cyanobacterial database (for Synechococcus elongatus PCC 7942). Each database integrates a variety of information including the genome, metabolic pathways, operons, protein features, Gene Ontology terms, and orthologs. Each of these databases received extensive literature-based curation to correct annotation errors and to integrate information about experimentally determined pathways and gene functions. For more information on these databases, click here. The curated databases are:
  • Synechococcus sp. WH 8102 (new)
  • Prochlorococcus marinus CCMP1375 (new)
  • Prochlorococcus marinus subsp. pastoris (strain CCMP1986) (new)
  • Synechococcus elongatus PCC 7942 (updated)

New in MetaCyc Version 24.0

MetaCyc now contains 2,801 metabolic pathways from all domains of life. MetaCyc contains the equivalent of 9,790 textbook-pages of mini-review summaries.

We have added and/or updated 49 pathways in MetaCyc since the last release.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

New in EcoCyc Version 24.0

• We imported five large acetylation datasets into EcoCyc in this release.
• In the 1970s, an enzyme that catalyzed the transfer of the aminocarboxypropyl group from S-adenosylmethionine to the N3 position of uridine within tRNAs was identified. However, the identity of the gene encoding this enzyme remained unknown. Recently, Takakura et al. and Meyer et al. both identified tapT (formerly known as yfiP) as the responsible gene.

• We have updated curation of the AlkB nucleic acid repair protein following a study by Reichle et al. identifying 2-thiocytidine-modified tRNA as a target of methylation damage and demonstrating AlkB-mediated repair.

• The representation of cytochrome bd-1 oxidase has been updated to include a previously unknown accessory subunit, CydH, identified in the cryo-EM structure reported by Safarian et al..

• Data from four high-throughput analyses, including RNA quadruplex structures (Shao et al.), RNA polymerase-binding RNA aptamers affecting gene expression (Magan et al.), the kinetics of gene expression after σ^E induction (Lacoux et al.), and the location of mRNAs inside the cell (Kannaiah et al.) has been incorporated into summaries.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

2. New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Improvements have been made to pathway layouts, as well as to display of chemical structures. Pathway diagrams can now depict pathways spanning multiple cellular compartments.

• The organism selector has new options for filtering the set of organisms displayed, such as to see genomes from the NCBI representative genomes set.

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Release Notes for BioCyc Version 23.5

Released on December 19, 2019.

Version 23.5 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 23.5 of BioCyc contains 17,043 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

• Bacillus subtilis 168
  • BsubCyc now contains the most recent available genome annotation (February 2018), enhanced by updates from the primary literature: 239 publications from 2018, 204 publications from 2019
  • We added experimental evidence to 21 gene products in BsubCyc

• Pseudomonas putida KT2440
  • We continued literature-based curation of this organism, upgrading a number of protein functions based on new literature information.
  • The database describes the regulation of 452 genes by 25 transcriptional regulators.

New in MetaCyc Version 23.5

MetaCyc now contains 2,766 metabolic pathways. The MetaCyc data were curated from 62,400 publications.

We have added and/or updated 28 pathways in MetaCyc since the last release.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

New in EcoCyc Version 23.5

Significant updates to EcoCyc include identification and characterization of YedK as a genome maintenance protein which forms covalent cross-links to abasic (apurinic/apyrimidinic) (AP) sites in ssDNA; identification of the new complex CRP-Sxy, which regulates some genes related to DNA uptake (natural competence); and identification of the HicB protein, known as the antitoxin of the HicA-HicB toxin-antitoxin system, as a transcription factor that autoregulates the transcription of the hicAB operon.

2. New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Exporting Pathway Collages to SVG files is now supported to enable higher quality images to be exported.

• BLAST search: We made several improvements to BLAST searches including adding the ability within the BLAST search page to select a different PGDB for searching other than the current PGDB.

• Favorites SmartTable: A "Favorites" SmartTable is now defined for each user. It is accessible through the "Add to SmartTable" button near the top of many pages.

• Pathway Evidence Report Sorted by Pathway Score: A new variant of the pathway evidence report available from command Analysis → Reports → Pathway Evidence sorts the report by pathway score to speed review of low-scoring pathways. Note that older BioCyc databases do not contain pathway scores.

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Release Notes for BioCyc Version 23.1

Released on September 19, 2019.

Version 23.1 is a minor release that includes updates to some of the databases at the BioCyc Web site and the corresponding downloadable data files.

Version 23.1 of BioCyc contains 14735 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

• Pseudomonas putida KT2440 -- We upgraded this database to the Tier-2 curation level. Strain KT2440 is the plasmid-free derivative of the toluene-degrading bacterium Pseudomonas putida mt-2, which was originally isolated in 1963 under the name Pseudomonas arvilla mt-2. Unlike strain mt-2, strain KT2440 does not carry the pWW0 TOL plasmid, which is required for toluene degradation. Strain KT2440 is the first Gram-negative soil bacterium to be certified as a safety strain by the Recombinant DNA Advisory Committee, and is considered the best characterized saprophytic Pseudomonad that has retained its ability to survive and function in the environment. It is used worldwide as a workhorse for genetic and physiological studies and for the development of biotechnological applications. Updates to the database include:
  • Propagation of cumulative changes in MetaCyc compounds and reactions, synchronizing the two databases.
  • Rerun of the pathway prediction algorithm, followed by human inspection and pruning of some of the predicted pathways. The pathway count grew by 25, for a total of 330. The number of enzymatic reactions grew from 2,081 to 2,313.
  • Creation of a large number of protein complexes, increasng the total number of complexes from 37 to 180.
  • Propagation of strain KT2440 enzymes that were previously curated in MetaCyc into this PGDB.
  • Curation of several new pathways that were previously not present in MetaCyc.
  • Literature-based curation of 65 proteins [click for listing]

• Saccharomyces cerevisiae S288c -- The YeastCyc database received a major overhaul; for details click here.

New in MetaCyc Version 23.1

MetaCyc now contains 2,749 metabolic pathways. The MetaCyc data were curated from 61,800 publications.

We have added 27 new pathways to MetaCyc since the last release. In addition, we significantly revised 12 pathways by modifying pathway diagrams, adding commentary, and updating enzyme and gene information.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

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Release Notes for BioCyc Version 23.0

Released on April 29, 2019.

Version 23.0 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 23.0 of BioCyc contains 14,728 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

• This release includes 170 newly generated PGDBs and 2,390 databases that were re-generated using the latest version of the PathoLogic software and the latest version of the MetaCyc pathway database.

• Salmonella strain LT2 (SENT99287) -- We added a new curated Tier 2 database for Salmonella enterica subsp. enterica serovar Typhimurium strain LT2. New gene functions that were curated with experimental evidence and citations for strain LT2 include:
  • Regulatory protein FimY
  • DNA recombinase Fin
  • Cysteine desulfhydrase CdsH
  • Acid-inducible arylsulfatase AslA
  • NADPH-dependent aldo-keto reductase STM2406
  • A role for GlnA in growth, motility and virulence as a function of glutamine availability
  • Cyclic di-guanylate phosphodiesterase STM0551
  • O-acetyl-serine N-acetyltransferase OatA
  • A key role for PduB in microcompartment assembly
  • Transporter of pantothenate precursors PanS
  • N-acetylneuraminate:Na⁺ symporter STM1128
  • Transcriptional repressor RamR
  • γ-L-glutamyl hydroxamate hydrolase YfeJ

  In addition, enzymes from strain LT2 that were previously curated in MetaCyc were propagated to this PGDB. Enzymes from other strains that were curated in MetaCyc were added as links to MetaCyc in this LT2 PGDB. Enzymes and proteins that were curated in the strain 14028S PGDB were added as hyperlinks in the new PGDB. The latter two categories were briefly annotated with a computational evidence code and citations. Additional enhancements to the new PGDB include: import of external database links, protein features and annotations from UniProt and Pfam; integration of functional annotations derived from BioCyc ortholog computations; and integration of gene functions with experimental evidence listed in Thiele et al 2011) and in Seif et al 2018.

• Salmonella strain 14028S (SENT588858) -- We updated the Tier 2 Salmonella enterica subsp. enterica serovar Typhimurium strain 14028S database with the following new gene functions:
  • Suppressor of flagellin production STM14_2047
  • Swarming motility proteins encoded by yhcO and STM14_1529
  • O-antigen phase variation complex OpvAB
  • Cpx activating connector-like factor A CacA
  • Virulence factors PagK, PagK2 and PagJ
  • Acid and osmotic stress response regulator OmpR.

• Staphylococcus aureus NCTC 8325 (gcf_000013425) -- We added 42 gene names to the Tier 2 Staphylococcus aureus subspecies aureus strain NCTC 8325 PGDB based on an update by AureoWiki in 2018).

New in MetaCyc Version 23.0

MetaCyc now contains 2,722 metabolic pathways. The MetaCyc data were curated from 60,000 publications.

We have added 23 new pathways to MetaCyc since the last release. In addition, we significantly revised 12 pathways by modifying pathway diagrams, adding commentary, and updating enzyme and gene information.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

New in EcoCyc Version 23.0

EcoCyc now contains the equivalent of 3,105 textbook-pages of mini-review summaries for genes, pathways, and regulatory interactions.

• The L-lysine degradation I pathway was significantly updated and extended. Knorr et al. elucidated the functions of several new enzymes in the pathway and showed that the pathway is utilized as an adaptation to stationary phase growth conditions.

• A new pathway, cadaverine biosynthesis, now shows the use of lysine decarboxylation to cadaverine as a mediator of acid resistance (AR4).

• We added 129 regulatory interactions from high-throughput analysis by Aquino et al. for the Nac transcriptional dual regulator.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

2. New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Pathway Covering: A new metabolomics analysis operation called Pathway Covering is available. It computes a minimal number of pathways that cover (contain) a supplied set of metabolites. See Analysis → Metabolomics Pathway Coverage.

• Reaction diagrams in reaction pages are now formatted using our improved graphics system.

• Speed improvements have been made to most queries within the Search menu.

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Release Notes for BioCyc Version 22.6

Released on December 12, 2018.

Version 22.6 is a minor release that includes updates to the BioCyc Web site and downloadable data files. This release does not include the downloadable Pathway Tools software; its next release is planned for March 2019.

Version 22.6 of BioCyc contains 14,560 Pathway/Genome Databases.

New in MetaCyc Version 22.6

MetaCyc now contains 2,698 metabolic pathways. The MetaCyc data were curated from 58,954 publications. We have added 12 new pathways to MetaCyc since the last release. In addition, we significantly revised 7 pathways by modifying pathway diagrams, adding commentary, and updating enzyme and gene information.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

New in EcoCyc Version 22.6

We have added 2 new pathways to EcoCyc since the last release. The EcoCyc data were curated from 36,151 publications.

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

Release Notes for BioCyc Version 22.5

Released on Sep 25, 2018.

Version 22.5 is a major release that includes updates to the BioCyc Web site and downloadable data files, and a new version of the downloadable Pathway Tools software.

Version 22.5 of BioCyc contains 14,560 Pathway/Genome Databases.

1. Improvements to BioCyc Databases

• This version includes 1500 newly generated databases and 800 databases that were re-generated using the latest version of the PathoLogic software and the latest version of the MetaCyc pathway database. All of the new and re-generated databases are microbial genomes from the Human Microbiome Project.

• We updated the Mycobacterium tuberculosis H37Rv PGDB with curation of 40 new experimentally determined gene functions (enzymatic and regulatory) from the scientific literature. We updated the external database links to Mycobrowser and the Protein Data Bank, and updated the Gene Ontology annotations. We also imported protein functions from UniProt for 136 uncurated proteins that were not annotated with a specific function. In addition, we upgraded the PGDB with data (e.g., corrected chemical structures and reactions) from the newly released MetaCyc version 22.5. Click here for a list of all Mycobacterium tuberculosis H37Rv genes with curated (experimentally studied) functions.

• We updated the Staphylococcus aureus NCTC 8325 PGDB. Click here for a list of all Staphylococcus aureus NCTC 8325 genes with curated (experimentally studied) functions. Recent curation included the genes:
  • fakA
  • fakB2
  • fakB1
  • gdpP
  • pde2

  and pathway staphylopine biosynthesis and associated enzymes encoded by genes:

  • cntK
  • cntL
  • cntM

  and pathway staphyloferrin B biosynthesis and associated enzymes encoded by genes:

  • sbnI
  • sbnA
  • sbnB
  • sbnE
  • sbnH
  • sbnF
  • sbnC

New in MetaCyc Version 22.5

MetaCyc now contains 2,666 metabolic pathways. The MetaCyc data were curated from 58,000 publications.

We have added 26 new pathways to MetaCyc since the last release. In addition, we significantly revised 19 pathways by modifying pathway diagrams, adding commentary, and updating enzyme and gene information.

For more details see https://BioCyc.org/metacyc/release-notes.shtml.

New in EcoCyc Version 22.5

EcoCyc now contains the equivalent of 3,105 textbook-pages of mini-review summaries for genes, pathways, and regulatory interactions.

New GenBank File for Escherichia coli K-12 MG1655 Released!

A new GenBank file of the E. coli K-12 MG1655 genome and annotation (U00096.3) was released on September 24, 2018. The updated genome annotation in this file was directly generated from EcoCyc Version 22.5 in a collaboration with Guy Plunkett III (University of Wisconsin), Andrea Auchincloss (UniProt/Swiss-Prot), and NCBI.

The most recent prior update to U00096.3 was released on August 1, 2014. The version suffix is changed only when the nucleotide sequence has changed -- thus the version number remains the same for this new release because no changes have been made to the nucleotide sequence. This new update does contain a large number of other changes based on publications in the past four years. The most significant updates include:

• Newly discovered gene functions, including gene and product name changes
• Newly discovered genes and gene products
• Updated gene product names to conform to UniProt and NCBI guidelines

Highlights of EcoCyc Database Improvements

• We have added gene and protein objects for 32 new small proteins recently identified by VanOrsdel et al.

• We have updated the drug efflux proteins represented in EcoCyc. Text summaries for 11 complexes and 40 proteins have been revised and/or updated; 19 new transport reactions, 30 compounds (antibiotics, dyes and other toxins) and just under 200 literature references were added to the database as part of this project. Click here for a SmartTable of all E. coli transporters of known function. A new function was also added to the small multidrug resistance (SMR) family transporter, Gdx (formerly SugE) - characterized by Kermani et al. as a proton-coupled guanidinium exporter.

• Fitzgerald et al. showed that binding sites for the alternative sigma factor FliA represent active promoters that transcribe highly unstable RNAs.

• Insertion sequences and prophages are now represented as database objects within EcoCyc, enabling their inclusion in the generated Genbank file.

• A number of crystal and solution structures for the transcription machinery and transcriptional regulators have been published, including:
  • RNA polymerase by Molodtsov et al. and Narayanan et al.
  • RcsB by Filippova et al.
  • CpxA/ CpxR by Mechaly et al.
  • PhoB by Kou et al.

• We have added one new pathway to EcoCyc: prenylated FMNH₂ biosynthesis

For more details see https://BioCyc.org/ecocyc/release-notes.shtml.

2. New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• New Search Commands: The following new search commands have been added:
  • Search for cryptic prophages via Search → Search DNA or RNA sites → Search by site type → Cryptic Prophages
  • Search for pseudogenes via Search → Search genes, proteins, or RNAs → Search/filter by type/subunits → Pseudogenes only

• Performance Enhancements: We have engineered a number of performance enhancements, particularly to decrease the time to generate gene pages.

• Pseudogenes: Our internal representations for pseudogenes have changed to provide more consistent and comprehensive treatment of pseudogenes.

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3. BioCyc Operations -- Monitoring the Error Log

Despite the extensive testing that we perform prior to every BioCyc and Pathway Tools release, software bugs appear in every new released version. An essential tool for helping us to identify and fix these bugs as quickly as possible is the BioCyc error log. Whenever an error occurs in our website, the software "catches" the error and records various information in a log file, including the URL of the web page from which the error originated, the error message, and a "stack backtrace". The backtrace is a listing of the procedure calls in progress at the time the error occurred -- a snapshot of the internal state of the software.

Our programming team receives an email each night containing a summary of the error log, which we inspect to determine what errors are occurring, and with what frequency. We pursue the most frequent errors first. In most cases we are able to fix the problem within a day, and issue a patch that is incorporated by our running web servers, and is loaded by remote users of Pathway Tools the next time they start the software.

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Release Notes for BioCyc Version 22.0

Released on April 24, 2018.

• Version 22.0 is a major release that includes updates to the BioCyc Web site, downloadable data files, and downloadable software/database bundles.

• Version 22.0 of BioCyc contains 13076 Pathway/Genome Databases.

• We added a curated database for Staphylococcus aureus NCTC 8325 to BioCyc.

• We added five additional pan-genome databases to BioCyc for Escherichia coli, Helicobacter pylori, Salmonella enterica, Shigella flexneri, and Vibrio cholerae.

• MetaCyc now contains 2,609 metabolic pathways; the MetaCyc data were curated from 55,600 publications. We added 37 new pathways to MetaCyc since the last release.

• EcoCyc now contains 347 metabolic pathways; the EcoCyc data were curated from 34,421 publications. We added 2 new pathways to EcoCyc since the last release.

New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Pathway regulation: Pathway diagrams can now include detailed regulatory information for each step that are taken from the regulatory data present within a given PGDB. From any pathway page, such as L-homoserine biosynthesis, click on the "Show Regulation Details" button above the pathway diagram to see transcriptional, translational and substrate-level regulators included in the diagram. This button will only be present if there is regulation data available for the pathway, and if the pathway is displayed at a detail level that shows enzyme names. Mouse over any regulator icon for more information. Mouse over regulation arrows to identify which ligands influence specific isozymes.

• Cellular Overview reborn: The BioCyc cellular overview (metabolic map) diagram has been re-engineered to use modern web graphics. See Metabolism → Cellular Overview. The graphics now look sharper, and you can zoom the diagram quickly using your mouse wheel (the +/- bar at the upper left provides finer zoom control). When using the diagram in its Omics Viewer mode to display transcriptomics or metabolomics data, the sliders at the top of the diagram enable you to optimize the diagram by controlling the opacity of the diagram, the thickness of all edges in the diagram, and the thickness of the highlighted edges in the diagram. Additional sliders in the omics dialog enable thresholding of what omics data are visible.

  New webinars are available to explain the usage of the basic Cellular Overview and how to analyze omics data with the Cellular Overview.

• Metabolic model fluxes on Omics Dashboard: A new method is available for viewing the fluxes computed by running BioCyc metabolic models. Previously, after running a metabolic model (command Metabolism → Run Metabolic Model), the user could display the computed fluxes on the Cellular Overview diagram. Now, a new button "Show Fluxes on Dashboard" enables the user to also display the fluxes on the Omics Dashboard tool. This tool enables the user to both view reaction fluxes aggregated at the pathway or subsystem level (e.g., to view the integrated behavior of all amino acid biosynthetic reactions), and to drill down to see fluxes for individual pathways and reactions.

New in EcoCyc Version 22.0

The EcoCyc data were curated from 33,000 publications.

Highlights of EcoCyc Database Improvements

• A new electron transport reaction has been added and assigned to the periplasmic protein Ccp (formerly YhjA), characterized by Kademian et al. as a cytochrome c peroxidase which uses membrane quinones for the reduction of hydrogen peroxide.

  Two new pathways have been added to EcoCyc to reflect Ccp's role in anaerobic respiration:

  • NADH to hydrogen peroxide electron transfer
  • glycerol-3-phosphate to hydrogen peroxide electron transport

• The curation of exodeoxyribonuclease V (RecBCD), rhomboid protease (GlpG) and K⁺-transporting P-type ATPase (KdpFABC) has been revised and updated for this release. Reactions catalysed by ExoV and GlpG are now more accurately represented, and literature coverage has been extended significantly for all three.

• 5-Oxo-L-proline is a cyclic metabolite that is deleterious to the cell. An ATP-dependent 5-oxoprolinase was recently discovered by Niehaus et al..

For more details see http://BioCyc.org/ecocyc/release-notes.shtml.

New in MetaCyc Version 22.0

MetaCyc now contains 2,609 metabolic pathways; the MetaCyc data were curated from 55,000 publications.

We have added 37 new pathways to MetaCyc since the last release. In addition, we significantly revised 8 pathways by modifying pathway diagrams, adding commentary, and updating enzyme and gene information, for a total of 45 new and updated pathways.

For more details see http://BioCyc.org/metacyc/release-notes.shtml.

Improvements to other BioCyc Databases in Version 22.0

• We generated 113 new Staphylococcus aureus PGDBs in BioCyc, bringing the total number of S. aureus strains in BioCyc to 242

• We regenerated the BioCyc PGDB for S. aureus NCTC 8325, and performed extensive literature-based curation of this strain. The database now cites more than 500 publications.
  • We integrated assigned gene names and protein functions from UniProt, AureoWiki, MetaCyc, the literature, and from the non-RefSeq GenBank file. We thank UniProt and AureoWiki for use of their data.
  • We curated many S. aureus genes, adding mini-review summaries, reactions, evidence codes, and literature citations.
  • We reviewed and updated transporters and their assigned transport reactions.
  • We updated links from the strain NCTC 8325 PGDB to other databases such as UniProt and AureoWiki.
  • We imported Gene Ontology annotations from UniProt.
• We generated new pan-genome databases in BioCyc, which now contains pan-genome databases for the organisms below (new organisms are in bold face). You can find them by entering "pan-genome" in the "change organism database" dialog.
  • Clostridioides difficile
  • Escherichia coli
  • Helicobacter pylori
  • Listeria monocytogenes
  • Mycobacterium tuberculosis
  • Pseudomonas aeruginosa
  • Salmonella enterica
  • Shigella flexneri
  • Vibrio cholerae

• The Bacillus subtilis database BsubCyc received pathway and enzyme curation. Click here for details.

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Release Notes for BioCyc Version 21.5

Released on November 28, 2017.

• Version 21.5 is a major release that includes updates to the BioCyc Web site, downloadable data files, and downloadable software/database bundles.
• Version 21.5 of BioCyc contains 10,980 Pathway/Genome Databases.
• MetaCyc now contains 2,609 metabolic pathways; the MetaCyc data were curated from 55,600 publications. We added 37 new pathways to MetaCyc since the last release.
• EcoCyc now contains 347 metabolic pathways; the EcoCyc data were curated from 34,421 publications. We added 2 new pathways to EcoCyc since the last release.

New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Omics Dashboard: The Dashboard is an interactive tool for exploration and analysis of gene-expression and metabolomics datasets (see Dashboard publication in Nucleic Acids Research). For more information see the Dashboard Help document and Webinar #7 describing the Omics Dashboard. New Dashboard features added in this version include the following.
  • Extended the list of top-level panels to include several panels of non-metabolic functions including a panel for sigma factor regulons
  • "Show Genes Not Present in any Subsystem" button generates a list of genes not mapped to any panel
  • Added ability to search for a given gene by name and have the Dashboard open the panel hierarchy to show that gene (see Search link at top of page)
  • The experiment legend is shown at top of every pane
  • New options for creating publication-quality diagrams:
    • "Hide Controls" option removes all option buttons. The user can also now hide the control panel accordion on the right of the page.
    • User can now specify y-axis legend
    • "Hide Panel" command is now present in every panel's Options menu to unshow the panel
  • Regulator panel: added disjunction option, added list of regulators to tooltip for gene
  • Handle multiple replicons when sorting by map position
  • Put tooltips on the genes in the operon diagrams, and made the diagrams clickable
  • Add ability to generate empty dashboard for explanatory purposes
  • Added "Panel Description" command to panel Options menu to let users find out which GO terms are being used to define a given segment within the dashboard
  • Pwy diagrams: color scheme cutoff now computed only from data in diagram.
  • When generating pathway collage from dashboard image, keep user-specified color scale

• Omics Pop-ups Use Google Charts: Previously the Omics Pop-ups used Adobe Flash, but as Flash is no longer supported by some browsers, we have re-implemented the Omics Pop-ups using Google Charts.

• Improved Graphics and Fonts: We have upgraded many additional Web visualizations produced by Pathway Tools in its web server mode to use modern graphics and fonts, including the genome browser; genome overview; transport reactions; operon diagrams; transcription-unit diagrams; functionally-linked gene cluster diagrams; gene-neighbor diagrams; mapped-genes diagram; protein features; and sequence diagrams for promoters, binding-sites, and attenuators.

New in EcoCyc Version 21.5

The EcoCyc data were curated from 33,000 publications.

Highlights of EcoCyc Database Improvements

• A new electron transport reaction has been added and assigned to the periplasmic protein Ccp (formerly YhjA), characterized by Kademian et al. as a cytochrome c peroxidase which uses membrane quinones for the reduction of hydrogen peroxide.

  Two new pathways have been added to EcoCyc to reflect Ccp's role in anaerobic respiration:

  • NADH to hydrogen peroxide electron transfer
  • glycerol-3-phosphate to hydrogen peroxide electron transport

• The curation of exodeoxyribonuclease V (RecBCD), rhomboid protease (GlpG) and K⁺-transporting P-type ATPase (KdpFABC) has been revised and updated for this release. Reactions catalysed by ExoV and GlpG are now more accurately represented, and literature coverage has been extended significantly for all three.

• 5-Oxo-L-proline is a cyclic metabolite that is deleterious to the cell. An ATP-dependent 5-oxoprolinase was recently discovered by Niehaus et al..

For more details see http://BioCyc.org/ecocyc/release-notes.shtml.

New in MetaCyc Version 21.5

MetaCyc now contains 2,609 metabolic pathways; the MetaCyc data were curated from 55,000 publications.

We have added 37 new pathways to MetaCyc since the last release. In addition, we significantly revised 8 pathways by modifying pathway diagrams, adding commentary, and updating enzyme and gene information, for a total of 45 new and updated pathways.

For more details see http://BioCyc.org/metacyc/release-notes.shtml.

Improvements to other BioCyc Databases in Version 21.5

• Approximately 2,000 BioCyc databases were re-generated from the latest RefSeq entries, using the latest version of the PathoLogic software against the latest version of the MetaCyc pathway database.

• The HumanCyc database received extensive updates, including addition of 12 new pathways and updates to include the UniProt human proteome set. Click here for details.

• The Bacillus subtilis database BsubCyc received pathway and enzyme curation. Click here for details.

Use wget to Download BioCyc Files

Our users are reporting frequent interruptions when downloading large BioCyc data files. Please use wget rather than a web browser to download large BioCyc files. wget uses longer timeouts than web browsers, and also can continue a download that was interrupted from where it left off.

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Release Notes for BioCyc Version 21.1

Released on August 15, 2017.

Version 21.1 is a minor release that includes updates to the BioCyc Web site and downloadable data files. This release does not include the downloadable Pathway Tools software; its next release is planned for November.

Version 21.1 of BioCyc contains 11,000 Pathway/Genome Databases (an increase of more than 1,500 organisms).

Significant Curation Updates in Version 21.1

• YeastCyc: We have added 3 new pathways to YeastCyc and updated the curation of multiple enzymes. We have also updated the database to contain recent updates to MetaCyc metabolites and reactions.
  New Pathways:
  • heme a biosynthesis
  • homofuraneol biosynthesis
  • tRNA-uridine 2-thiolation (yeast mitochondria)

New in EcoCyc Version 21.1

• Three new pathways have been added to EcoCyc:
  • L-cysteine biosynthesis VII
  • lipoprotein posttranslational modification
  • tRNA-uridine 2-thiolation (bacteria)

• New information has been added for several membrane proteins including YhhQ - implicated in the uptake of queuosine precursors for salvage; MgtS (formerly YneM) - required for accumulation of the magnesium transporter MgtA under magnesium limiting conditions, and YbaT - which, along with glutaminase I, functions to overcome disrupted glutamate synthesis under copper stress conditions.

• The curation of DNA repair proteins AlkB and Endonuclease VIII has been revised and updated for this release; reactions catalyzed by these enzymes are now accurately represented and literature coverage has been extended significantly.

For more details including database statistics see http://BioCyc.org/ecocyc/release-notes.shtml

New in MetaCyc Version 21.1

We have added 45 new pathways to MetaCyc since the last release. In addition, we significantly revised 13 pathways by modifying pathway diagrams, adding commentary, and updating enzyme and gene information, for a total of 58 new and updated pathways. We also added commentary to 11 existing superpathways.

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Release Notes for BioCyc Version 21.0

Released on April 27, 2017.

• Version 21.0 is a major release that includes updates to the BioCycWeb site and downloadable data files, and a new version of the downloadable Pathway Tools software.
• Version 21.0 of BioCyc contains 9,389 Pathway/Genome Databases.
• In EcoCyc we added one new pathway, updated curation of proteins belonging to the ABC family of transporters, revised text summaries for 59 complexes and 209 proteins, and added over 300 references.
• MetaCyc now contains 2,526 metabolic pathways. The MetaCyc data were curated from 52,000 publications.

New in the Biocyc Website

• Omics Dashboard: The Dashboard is an interactive tool for exploration and analysis of gene-expression and metabolomics datasets. For more information see Webinar #7 describing the Omics Dashboard
• Improved Graphics and Fonts: We have upgraded some of the visualizations produced by Pathway Tools in its web server mode to use modern graphics and fonts, such as the Regulation Summary Diagram on gene pages.
• Multi-Organism Metabolic Route Search: The metabolic route search capability has been extended to enable searches across organism communities

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Release Notes for BioCyc Version 20.5

Released on December 17, 2016.

• Version 20.5 is a major release that includes updates to the BioCyc Web site, downloadable data files, and downloadable software/database bundles.
• Version 20.5 of BioCyc contains 9,387 Pathway/Genome Databases.
• MetaCyc now contains 2,507 metabolic pathways; the MetaCyc data were curated from 51,500 publications. We added 11 new pathways to MetaCyc since the last release.

New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Receive Notification of Database Updates -- This new facility allows scientists to sign up to be notified of curation of new information in their research interest area(s). Sign up via the Update Notifications Page (available through Analysis → Update Notifications) to be notified when new curation (which indicates new published experimental findings) occurs for specific genes or metabolic pathways. You can also sign up for notifications in interest areas specified by Gene Ontology terms, such as cell motility or cell division -- you will then be notified whenever new curation occurs in genes involved in those biological processes. Notifications will be sent by email in conjunction with BioCyc releases.

• Expanded Organism Searches: The "search by organism properties" option within the organism selector menu in the upper-right corner of most BioCyc pages includes additional searches to enable users to find BioCyc databases based on the amount of data of different types present in the database, including:
  • Number of Gene Ontology terms
  • Number Phenotype Microarray datasets
  • Number of gene essentiality datasets
  • Number of genes with essentiality data
  • Number of transcriptional regulatory interactions (i.e., size of regulatory network present)

• Revised Protein Feature Coloring: We have revised the coloring scheme within the protein-feature display to assign a fixed set of colors to different feature types. For example, all enzyme active site features will be colored purple.

Significant Curation Updates in Version 20.5

• Updates to BsubCyc Bacillus subtilis 168 Database. Updates included addition of two new transcription factors, five transcription units, and seven transcription start sites with experimental evidence. 22 additional proteins are now associated with one or more GO terms with experimental evidence, and 85 new citations were added to papers published in 2016, for a total of 163.

  Example updates include include the transcription factors ThrR, GabR, the regulator of DNA replication initiation YabA, the YaaT-YlbF-YmcA regulatory complex, and the bacillithiol biosynthesis enzyme L-malate glycosyltransferase.

• We created and refined new Tier 2 PGDBs for the following human microbiome bacteria. We reviewed and curated enzyme-reaction assignments and inferred pathways, reviewed computationally inferred transport reactions, and executed the Pathway Tools pathway hole filler.
  • Desulfovibrio piger ATCC 29098
  • Faecalibacterium prausnitzii A2-165
  • Prevotellacopri DSM 18205
  • [Clostridium] symbiosum WAL-14163

New in EcoCyc

New in MetaCyc

New Pan-Genome Databases in BioCyc

We created three new pan-genome databases in BioCyc, adding to the Mycobacterium tuberculosis pan-genome database released in the previous version of BioCyc. Each pan-genome database integrates genes and pathways from multiple strains within BioCyc to provide a global view of the genomes available for that species.

Organism	Number of Strains
Pseudomonas aeruginosa	23
Peptoclostridum difficile	10
Listeria monocytogenes	35

New Gene Essentiality Datasets in BioCyc

We have loaded additional gene essentiality data from the OGEE database into BioCyc databases. These data were originally published in the primary literature, and were then aggregated by OGEE.

The following organism databases include the newly added gene essentiality data. To access a given gene essentiality dataset, click on the Growth-Media page for a given organism below, and then click on a growth medium to see a list of all genes that are essential in that medium. In additional, gene pages list essentiality data for that gene when available.

Organism	# Datasets
Acinetobacter baumannii ATCC 17978	2
Acinetobacter sp. ADP1	1
Agrobacterium fabrum C58	1
Brevundimonas subvibrioides ATCC 15264	1
Burkholderia cenocepacia J2315	1
Caulobacter crescentus NA1000	1
Escherichia coli CFT073	1
Escherichia coli K-12 substr. MG1655 (EcoCyc	5
Escherichia coli O25b:H4-ST131	1
Francisella tularensis novicida U112	2
Haemophilus influenzae Rd KW20	1
Helicobacter pylori 26695	2
Homo sapiens	1
Mycobacterium tuberculosis H37Rv	4
Mycoplasma genitalium G37	1
Mycoplasma pulmonis UAB CTIP	1
Porphyromonas gingivalis ATCC 33277	1
Pseudomonas aeruginosa PAO1	2
Pseudomonas aeruginosa UCBPP-PA14	3
Rhizobium leguminosarum bv. viciae 3841	1
Rhodopseudomonas palustris CGA009	1
Saccharomyces cerevisiae S288c	1
Salmonella enterica enterica serovar Typhi str. CT18	1
Salmonella enterica enterica serovar Typhi str. Ty2	1
Salmonella enterica enterica serovar Typhimurium str. 14028S	4
Salmonella enterica enterica serovar Typhimurium str. LT2	1
Salmonella enterica enterica serovar Typhimurium str. SL1344	4
Shewanella oneidensis MR-1	1
Sphingomonas wittichii RW1	1
Staphylococcus aureus aureus NCTC 8325	2
Streptococcus pneumoniae D39	1
Streptococcus pneumoniae R6	1
Streptococcus pneumoniae TIGR4	1
Synechococcus elongatus PCC 7942	1

Release Notes for BioCyc Version 20.1

Released on Sep 29, 2016.

• Version 20.1 is a minor release that includes updates to the BioCyc Web site and downloadable data files.
• Version 20.1 of BioCyc contains 7,600 Pathway/Genome Databases.
• In EcoCyc we added two new pathways and revised several periplasmic proteins.
• MetaCyc now contains 2,492 metabolic pathways; the MetaCyc data were curated from 50,700 publications. We added 38 new pathways to MetaCyc since the last release.

New Gene Essentiality Datasets in BioCyc

We have loaded gene essentiality data from the OGEE database into BioCyc databases. These data were originally published in the primary literature, and were then aggregated by OGEE.

To access a given gene essentiality dataset, click on the Growth-Media page for a given organism below, and then click on a growth medium to see a list of all genes that are essential in that medium. In additional, gene pages list essentiality data for that gene when available.

• Acinetobacter sp. ADP1
• Homo sapiens
• Francisella tularensis novicida U112
• Haemophilus influenzae Rd KW20
• Helicobacter pylori 26695
• Mycobacterium tuberculosis H37Rv
• Mycoplasma genitalium G37
• Mycoplasma pulmonis UAB CTIP
• Pseudomonas aeruginosa UCBPP-PA14
• Saccharomyces cerevisiae S288c
• Salmonella enterica enterica serovar Typhi str. CT18
• Salmonella enterica enterica serovar Typhimurium str. LT2
• Staphylococcus aureus aureus NCTC 8325
• Streptococcus pneumoniae D39
• Streptococcus pneumoniae R6
• Streptococcus pneumoniae TIGR4

Significant Curation Updates in Version 20.1

• We created and refined a new Tier 2 PGDB for Lactobacillus rhamnosus GG, a human microbiome organism and a well documented probiotic strain. Refinements include review of inferred pathways, review of inferred transport reactions, and supervised execution of the Pathway Tools pathway hole filler.

• New curation added to the Tier 2 PGDB for Corynebacterium glutamicum ATCC 13032 includes a superpathway for aromatic compound degradation and a biosynthetic pathway for the cyclic C50 carotenoid decaprenoxanthin. A number of enzymes and transporters associated with these pathways were also curated. Other newly curated enzymes and transporters include Ldh, LldD, Dld, CglK, Kup and BetP.

New in EcoCyc

New in MetaCyc

Release Notes for BioCyc Version 20.0

Released on May 9th, 2016.

• Version 20.0 of BioCyc contains 7,600 Pathway/Genome Databases.

• EcoCyc now contains the equivalent of 2,700 textbook-pages of mini-review summaries. The EcoCyc data were curated from 31,000 publications.

• MetaCyc now contains 2,400 metabolic pathways; the MetaCyc data were curated from 49,000 publications. We added 44 new pathways to MetaCyc since the last release. In addition, we significantly revised 21 pathways by adding commentary and updated enzyme and gene information.

New in the Biocyc Website

The following new features are present in the BioCyc website, and are thus available to all databases within the BioCyc collection:

• Run metabolic models using web interface: You can now run metabolic models via the BioCyc website with a few mouse clicks, as follows:
  • Find BioCyc organisms with metabolic models by clicking "change organism database", then select the tab "Having Metabolic Models". Click the organism for which you want to run a model and click OK.
  • Then run command Metabolism ? Run Metabolic Model and follow the instructions.
  • Example: Click here to run the EcoCyc metabolic model.
  • Models are available on BioCyc.org for two other gut-microbiome bacteria.

• Metabolic and genome posters for all BioCyc organisms are available -- see the commands Metabolism ? Generate Metabolic Map Poster and Genome ? Generate Genome Poster.

• Re-designed metabolite pages: BioCyc metabolite pages have been re-designed to structure metabolite information across multiple tabs to make information easier to find and assimilate.

• Search for DNA sites: The new command Search ? Search DNA or mRNA Sites enables searches for sites such as promoters and attenuators, potentially filtering by replicon, nucleotide coordinates, and ligands.

• Pathway Perturbation Scores: The command to generate a table of pathways overlaid with omics data now ranks pathways by Pathway Perturbation Score, a new score that attempts to measure the degree to which the expression level of a pathway is perturbed over the course of an omics experiment. From the website Metabolism ? Cellular Overview page, select "Upload Data from File" and ask to show the data as a table of pathway diagrams.

• New Cellular Overview highlighting commands: Several new commands are available to help you find information within the Cellular Overview (metabolic map) diagram. Under the right-sidebar menu, see these new commands:
  • Highlight reaction by enzyme cellular location
  • Highlight reaction by modulation (finds reactions according to substrate-level regulation of enzyme activity)
  • Highlight enzyme by curation

• Gene/reaction schematic improvements: The gene/reaction schematic diagram has been improved to reduce the size of large tangled sets of gene-reaction relationships by truncating such diagrams. A button is now provided to allow the user to toggle between full and truncated versions of the diagram.

• Improved command to Search for Reactions by Substrates: This command, which enables users to search for reactions by specifying one or more substrates, now enables users to specify which side of the reaction different substrates are on, relative to each other (see Search ? Search Reactions).

• New Pathway Collages page: The new page Metabolism ? Pathway Collages enables users to generate a pathway collage (a personalized multi-pathway diagram) by selecting from a list of all pathways in the current database.

Significant Curation Updates

• Corynebacterium glutamicum: Included in this BioCyc release is a new curated (Tier 2) PGDB for the industrially important organism Corynebacterium glutamicum ATCC 13032. This organism is used in the engineered production of amino acids and other compounds. The PGDB is based on GenBank record BA000036.3, but also incorporates some gene function annotations from GenBank record BX927147.1. It contains over 200 inferred pathways and 92 inferred transport reactions. We performed a thorough review of the PathoLogic pathway prediction, manually assigned a number of enzymes to their catalyzed reactions, and performed literature searches and curation for a number of enzymes. We will continue curation on an ongoing basis.
• Mycobacterium tuberculosis: A curated database for the H37Rv strain was launched in February 2016. This database, BioCyc MtbH37Rv, was generated from Genbank record AL123456.3, which was revised in December 2012 to contain the latest annotation from Tuberculist. We performed literature searches and curation for 155 proteins, resulting in the addition of 55 textbook-page equivalents of mini-reviews to these proteins. The database cites 1,700 literature references from which the enhanced curation was derived. Literature curation was added for 34 metabolic pathways, including authoring of 32 textbook-page equivalents of mini-reviews to these pathways. Drug screening data for more than 700 compounds, assembled by Ekins et al (J Cheminform 5(1):13 2013), has been included in BioCyc MtbH37Rv; those compounds are listed under the compound class "anti-tuberculosis compound" (see the Ontology tab).

Release Notes for BioCyc Version 19.5

Released on Nov 12, 2015.

• Version 19.5 of BioCyc contains 7,667 Pathway/Genome Databases.

• This version of BioCyc contains a new pan-genome Pathway/Genome Database for Mycobacterium tuberculosis that integrates genes from 25 M. tuberculosis strains into one database. That PGDB also contains the pathways predicted from this multi-strain gene set. For more information about pan-genome PGDBs, click here. To select this PGDB, search for "pan-genome" in the organism selector.

• This new release includes 2 new pathways in EcoCyc.

• MetaCyc now contains 2,411 metabolic pathways and 13,074 reactions; its contents have been curated from over 47,800 publications.

BioCyc Web Site Improvements

• Redesigned gene pages: We have redesigned the Web gene pages for a more modern look and to make information easier to find. Gene pages now contain a series of tabs; clicking on a given tab shows a specific type of information, such as the reactions catalyzed by a gene product, the GO terms assigned to the gene, or the features defined for the gene product. Note that the set of tabs present varies depending on the type of the gene product and the information available. The "Show All" tab combines all information in one page for easier searching.

• New pathway collage feature: A pathway collage is a diagram depicting a set of connected metabolic pathways, possibly with omics data superimposed (example here). You can now interactively create a pathway collage in Pathway Tools desktop and Web modes. To create a pathway collage in Web mode:
  • (Optional) Load a gene expression or metabolomics data file if you want to include such data within your collage, by bringing up the cellular overview (Metabolism → Cellular Overview) and then running Right-Sidebar Menu → Overlay Experimental Data (Omics Viewer) → Upload Data from File.

  • Specify the pathways to include in the collage in one of two ways:
    • Go to any pathway page and then invoke Right-Sidebar Menu → Generate Pathway Collage.
    • Create a SmartTable containing the pathways to include in the collage and then invoke Right-Sidebar Menu → Export → Export Pathways to Pathway Collage.

  • The collage will be created in your web browser, where you will be able to reposition the pathways interactively, add additional pathways to the collage, add connections between metabolites, change various display styles, and view omics data, to create your desired diagram. Export the diagram to a file for inclusion in a publication. For more details see the Website User's Guide.
• New Cellular Overview queries: New Web Cellular Overivew query operations include:
  • Highlight Genes → By replicon and By Regulon
  • Highlight Reactions → By Evidence
  • Highlight Pathways → By Curation and By Evidence.

• Many performance improvements and bug fixes have been made to SmartTables.

• Performance improvements have been made to Search → Cross Organism Search.

Desktop Mode Improvements to the Downloadable Pathway Tools Software

The MetaFlux metabolic-modeling module has undergone the following enhancements:

• Dynamic FBA: MetaFlux can now perform dynamic FBA in addition to the previous steady-state FBA. In dynamic FBA, a steady-state metabolic model can be executed across multiple time steps File enzymes-table.shtml not found for system biocyc! Aborting!Dynamic FBA can be applied to single organisms or to organism communities to predict changes in organism abundance over time. New nutrients and organisms can be introduced at specific grid points and specific times during a simulation.

• Model a spatial grid: Models can now be executed across a user-defined rectangular grid in addition to the previous single spatial compartment. Diffusion of cells and small molecules is simulated across the grid.

• New graphical outputs: Model results can be viewed using several new tools such as viewing the time course of organism biomass changes and metabolite concentration changes, both overall, and across the grid. Results can be viewed as static X-Y plots and as MetaFlux-generated videos.

Full Pathway Tools release notes: http://bioinformatics.ai.sri.com/ptools/release-notes.shtml

EcoCyc release notes: http://ecocyc.org/release-notes.shtml

MetaCyc release notes: http://metacyc.org/release-notes.shtml

Release Notes for BioCyc Version 19.1

Released on June 24, 2015.

Version 19.1 of BioCyc contains 5,711 Pathway/Genome Databases.

This new release includes eight new pathways in EcoCyc.

MetaCyc now contains 2,363 metabolic pathways and 12,700 reactions; its contents have been curated from over 46,000 publications.

Release Notes for BioCyc Version 19.0

Released on March 20, 2015.

Version 19.0 of BioCyc contains 5,500 Pathway/Genome Databases.

BioCyc Web Site Improvements

• Genome browser: The Pathway Tools genome browser now depicts transcription factor binding sites and attenuators, and will display the nucleotide sequence at high magnification levels.

• Sequence variant data analysis: Web SmartTables support a new analysis operation for sequence variant data. The user can define a SmartTable of replicon regions and associated sequence variants via a file import operation. Then, the SmartTables transformation "Sequence -- nearest gene to DNA region" adds additional columns to the SmartTable showing the nearest gene to each region, and the amino-acid change caused by each sequence substitution.

Desktop Mode Improvements to the Downloadable Pathway Tools Software

• Sequence Editor: A new interactive sequence editing tool is available for making manual updates to a replicon sequence. See Chromosome → Edit Nucleotide Sequence.

• MetaFlux Metabolic Modeling Tool
  • Model development mode now includes reporting of blocked reactions, and improved taxonomic reaction information when gap filling.

  • Several improvements have been made to display of reaction fluxes on the metabolic map diagram.

Transcriptional Regulation Data Imported from RegTransBase and TractorDB

• RegTransBase is a database of prokaryotic transcriptional regulation manually curated from the literature. Data describing approximately 2100 transcription-units, 1100 promoters and 1300 transcription factor binding sites across 149 organisms, including literature citations, were imported from RegTransBase into BioCyc. About a third of the imported data pertains to just three organisms: Corynebacterium glutamicum ATCC 13032, Pseudomonas aeruginosa PAO1, and Streptomyces coelicolor A3(2). This information is visible on the gene page for both transcriptional regulators and genes regulated by transcriptional regulators (e.g. RhlR), with more details on the transcription-unit page (e.g. rhlR transcription unit).
• TractorDB is a database of computationally predicted transcription factor regulatory sites in a handful of gamma-proteobacteria. Approximately 9000 predicted regulatory interactions across 25 organisms were imported from TractorDB into BioCyc.

Full Pathway Tools release notes: http://bioinformatics.ai.sri.com/ptools/release-notes.shtml

EcoCyc release notes: http://ecocyc.org/release-notes.shtml

MetaCyc release notes: http://metacyc.org/release-notes.shtml

Release Notes for BioCyc Version 18.5

Released on Nov 07, 2014.

Version 18.5 of BioCyc contains 5,500 Pathway/Genome Databases.

BioCyc Web Site Improvements

• Metabolomics and gene expression operations: Muliple new metabolomics and gene-expression operations are available in web and desktop modes.

• More flexible omics-data file formats: We have extended the BioCyc omics-data loading software to recognize a wider variety of gene and metabolite names and identifiers in the first column of the file.

• Quick Search locus IDs: The Web quick-search box now accepts an additional search option: enter a gene locus ID from any BioCyc genome, regardless of the currently selected organism. Example: entering MSM_0046 will find an NADH oxidase in Methanobrevibacter smithii.

• Omics popups on pathway pages: The pathway customization options have been extended to support upload of omics datasets with multiple timepoints, displayed using omics popups. Visit any pathway page and choose the "Customize or Overlay Omics Data on Pathway Diagram" operation.

• iPhone/iPad app generalized to access any PGDB in any pathway tools web server: Initially, our EcoCyc app provided access to the EcoCyc database only, on the iPhone only. Then we expanded it to work on the iPad. In this release we have renamed the app "BioCyc," and it now enables users to access any database in BioCyc, and any database in any other Pathway-Tools-based website that is running version 18.5 or later of Pathway Tools.

Desktop Mode Improvements to the Downloadable Pathway Tools Software

• PythonCyc: A new Python API is available for Pathway Tools. It supports programmatic querying and updating of PGDBs via Python. For more information, see the PythonCyc Overview page.

• MetaFlux Metabolic Modeling Tool
  • Metabolic models of organism communities: MetaFlux now supports construction of quantitative metabolic models for communities of organisms, such as bacteria within the human microbiome.

  • Inference of biomass metabolite list: MetaFlux can now generate a suggested biomass metabolite list for many organisms by using biomass compositions recorded for nine different taxonomic groups.

Full Pathway Tools release notes: http://bioinformatics.ai.sri.com/ptools/release-notes.shtml

EcoCyc release notes: http://ecocyc.org/release-notes.shtml

MetaCyc release notes: http://metacyc.org/release-notes.shtml

Release Notes for BioCyc Version 18.1

Released on June 23, 2014.

Version 18.1 of BioCyc contains 3,563 Pathway/Genome Databases.

Release Notes for BioCyc Version 18.0

Released on March 24, 2014.

Version 18.0 of BioCyc contains 3,531 Pathway/Genome Databases.

BioCyc Web Site Improvements

• Cross-Organism Search: This new tool enables name-based searches across specified sets of organisms in BioCyc. For example, you can search a specified taxonomic group in BioCyc (e.g., all cyanobacteria) for metabolites (or proteins, or pathways) having a certain substring in their name (e.g., achromobactin).

• Groups / SmartTables Enhancements:
  • Groups have been renamed to SmartTables.
  • Given a SmartTable containing genes or proteins, you can invoke a multiple sequence alignment for those genes or proteins
  • The SmartTable right-sidebar menus have been re-organized.
  • The icons in column headers have been re-organized with some options moved to the right-sidebar menus. A new collapse-column option is available.
  • Several performance improvements have been made for large SmartTables
  • Added support for peptide regions as a SmartTable object type.

• Sequence pattern searches: You can now search a genome for exact or degenerate short patterns of nucleotides or amino acids.

• Sequence alignments: You can now obtain multiple sequence alignments for genes and proteins, both within a genome and across genomes.

Desktop Mode Improvements to the Downloadable Pathway Tools Software

• Quicksearch: The new desktop quicksearch toward the bottom left of the screen is analogous to the web quicksearch: it performs a substring search with the user's input word(s) against the names of most entities in the current PGDB, including genes, compounds, and pathways.

• SBML Import Tool: A new tool allows you to import an SBML file into a new or existing PGDB. The tool creates all metabolites and reactions defined in the SBML file in the PGDB, and attempts to map those metabolites and reactions to metabolites and reactions in MetaCyc.

Full Pathway Tools release notes: http://bioinformatics.ai.sri.com/ptools/release-notes.shtml

EcoCyc release notes: http://ecocyc.org/release-notes.shtml

MetaCyc release notes: http://metacyc.org/release-notes.shtml

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Release Notes for BioCyc Version 17.5

Released on October 11, 2013.

Version 17.5 of BioCyc contains 2,988 Pathway/Genome Databases.

BioCyc Web Site Improvements

• New Right-Sidebar Menu: The previous object-specific menus have been replaced by a right-sidebar menu of operations that changes depending on what type of page the user is visiting. For example, the menu of operations differs for pathway pages versus metabolite pages. Some operations previously accessible by buttons (e.g., retrieving a protein sequence) are now accessible through this new right menu in gene pages. If you do not see the menu, please reload the page in your web browser while holding down the "Shift" key.

• Web Cellular Overview and Omics Viewer: This tool has undergone a major overhaul including
  • It runs much faster and many bug fixes have been made
  • Gene expression data to be displayed on the Cellular Overview can now be retrieved from PortEco, from GEO, and from Web Groups
  • Pop-up improvements
  • Many new search commands are available
  • Labels for pathway groups are now included in the diagram

• Groups Enhancements: A number of enhancements have been made to both Web Groups including:
  • Groups can now be published. Once published a group is publically readable, and the group cannot be deleted, even by its owner. The idea is to encourage scientists to refer to published groups in their scientific publications.
  • Users can now create temporary groups without creating a BioCyc account to facilitate experimentation with Groups.
  • Database identifiers in database links can be added as groups columns, e.g., KEGG IDs for BioCyc compounds.
  • A group of objects can be created via text entry.
  • New row selection operations are available.
  • The star in the heading of the first column allows the user to toggle between viewing object names and object identifiers.

• Full Pathway Tools release notes: http://bioinformatics.ai.sri.com/ptools/release-notes.html

EcoCyc release notes: http://ecocyc.org/release-notes.shtml

MetaCyc release notes: http://metacyc.org/release-notes.shtml

Release Notes for BioCyc Version 17.0

Released on March 29, 2013.

Version 17.0 of BioCyc contains 2,920 Pathway/Genome Databases.

BioCyc Web Site Improvements

• Groups Enhancements: A number of enhancements have been made to both Web Groups and Desktop Groups including re-organization of Web Groups menus and addition of new transformations.

• Phenotype Microarrays and Other Growth Data: The displays of growth media, growth observations, and phenotype microarray data has been substantially revised.

• Metabolic Route Search: The new RouteSearch tool, accessible from command Tools -> Metabolic Route Search, supports two types of searches in metabolic networks: within organism searches and synthetic pathway searches. For both types of search, the user specifies a starting and endingmetabolite of interest, and the software generates alternative reaction pathways connecting those metabolites.

• Web Omics Pop-ups: When using the Cellular Omics Viewer you can view a graph of omics data (e.g., plotting gene-expression data over time for a given gene). To do so, paint expression data on the Cellular Overview. Then mouse over a reaction (or metabolite) of interest. Click "Omics" in the menu of the resulting pop-up window, which will graph the omics data for that reaction.

• Web images: Several performance improvements were made to web images and web image generation now works on Windows-64.

Desktop Mode Improvements to the Downloadable Pathway Tools Software

• Rate-Limiting Reactions: A reaction can now be designated as rate limiting with respect to a given metabolic pathway, using the pathway editor.

• PGDB Registry Speedups: As the number of PGDBs in the registry grew, the speed of the registry became far too slow; the registry interface has been re-designed so that finding PGDBs within the registry is much faster.

• Path

  ch faster.oLogic: Pathologic can now compute abundance scores for pathways based on gene abundance values provided in input files. We have also made extensive imp

  that finding PGDBs within the registry is much faster.rovements to the name matcher that increase its sensitivity (recognition of enzyme names) with little if any decrease in its specificity.

• Metaflux: Several performance and user interface improvements were made to MetaFlux.

• New Installer: A new cross-platform installer is used for Pathway Tools.

Release Notes for BioCyc Version 16.5

Released on November 15, 2012.

Version 16.5 of BioCyc contains 2,038 Pathway/Genome Databases.

BioCyc Web Site Improvements

• Phenotype Microarrays and Other Growth Data: The displays of growth media, growth observations, and phenotype microarray data has been substantially revised.

• Atom Mappings: MetaCyc now contains atom mapping data for thousands of reactions. Atom mappings define the correspondence between atoms in the reactants of a chemical reaction, and the atoms in the products of that reaction.

• New representation of EC Numbers in Pathway Tools: Clicking on the EC number from a reaction page navigates to an EC-number page. The difference is more obvious if a reaction is associated with multiple EC numbers. In these cases all of the EC numbers, along with their names, comments, citations, etc., appear on the reaction page.

• Many Web Groups Enhancements: Many new transformations have been added/renamed.

• Customize Pathway Diagram with Omics Data: The command Pathway → Customize Pathway Diagram now includes an option for painting omics data onto an individual pathway diagram.

• Web Omics Viewer Displays Table of Pathways: The Cellular Omics Viewer (see Cellular Overview → Overlay Experimental Data) now includes an option previously present in the desktop version, namely to generate a table displaying omics data painted onto diagrams of individual pathways. This option can be selected from the "Show data:" selector in the Omics Viewer dialog.

Desktop Mode Improvements to the Downloadable Pathway Tools Software

• MetaFlux for Windows: The MetaFlux component of Pathway Tools for building steady-state metabolic flux models now runs under Windows in addition to Linux and Mac.

• Save Display State: You can now save the display state of Pathway Tools for later restoration by you or by someone you send a display-state file to.

• Captions in Cellular Omics Viewer: You can add captions for elements of the Cellular Overview diagram by right-clicking on a metabolite or a reaction and selecting Show Caption.

• Glycan Structures: Pathway Tools now supports display and editing of glycan structures.

Release Notes for BioCyc Version 16.0

Released on February 16, 2012.

Version 16.0 of BioCyc contains 1,763 Pathway/Genome Databases, including 414 complete bacterial genomes from the Human Microbiome Project.

In this release of BioCyc, our E. coli W3110 database has undergone significant enhancements under funding from the PortEco project. We performed an annotation normalization of W3110 with respect to EcoCyc (which describes strain MG1655). The purpose of this project was to modernize the annotation of W3110 with respect to the frequently updated EcoCyc annotation, and to remove spurious differences in annotations between the two strains (e.g., different protein names for proteins having the same function).

BioCyc Web Site Improvements

• Improved chemical graphics: The graphic display of chemical structures on compound and reaction pages has been re-implemented using the SVG web standard, resulting in higher quality graphics. (This improvement is currently visible only to users using recent versions of Firefox.)

• New multi-organism selector: A new multiple organism selector dialog is now available when performing comparative operations, such as using the comparative genome browser, and showing information about a given gene or pathway across multiple organisms. The new dialog is much faster and easier to use than the older selector page.

• Highlighting large groups: Previously, when painting a group (such as a gene group) to the web Cellular Overview, only short groups (of length < 100) were supported. Now this operation will work for arbitrarily long groups.

• A spelling corrector is now used during web searches.

Desktop Mode Improvements to the Downloadable Pathway Tools Software

• MetaFlux FBA Module Available on More Platforms: MetaFlux now runs on MacOS, and it runs on older versions of Linux-64 than it did previously.

Release Notes for BioCyc Version 15.5

Released on October 21, 2011.

Version 15.5 of BioCyc contains 1,700 Pathway/Genome Databases, including 414 complete bacterial genomes from the Human Microbiome Project.

The HumanCyc database has been promoted to a Tier 1 database to reflect the significant curation that HumanCyc has undergone during the last two years, and to reflect the creation of a flux-balance analysis model from HumanCyc.

BioCyc Web Site Improvements

• Web Object Groups: A web implementation of the object groups facility now exists. Users can define groups of objects of interest (such as a list of genes or metabolites), either by entering them manually or by defining groups from query results. Users can operate on web groups in a variety of ways, such as painting all objects in a group on an overview diagram, or transforming an object group (such as transforming a group of one or more genes to a group containing the one or more pathways involving those genes). Enrichment analyses can be performed on object groups (such as determining whether a gene group is over-represented for a set of pathways or a set of Gene Ontology terms). Object groups can be private, or users can share object groups with other specific users, or make them public. See Tools → Groups and the Groups Webinar.

• Taxonomic Organism Selector: The web "change organism database" dialog now provides a new mode of selecting organisms by taxonomic group; click on the "By Taxonomy" tab at the top of the selection dialog.

• Improved Nucleotide Sequence Selector: The web button "Nucleotide Sequence, Advanced" on gene/protein pages has been improved to allow specification of the desired sequence in terms of absolute coordinates as well as relative coordinates upstream and downstream of the starting gene.

• New Web Services: Web services allow Internet-based querying of BioCyc data. Several new web services have recently been added. See the appropriate section in the Website User Guide for more details.
  One application using the Pathway Tools Web services is the bioCycPlugin for Cytoscape.

• Growth Medium Search: The new command Search → Growth Media enables searching for growth media in the current PGDB according to several criteria.

• Improvements to Generic Reactions: Generic reactions in PGDBs are reactions whose classes are substrates, such as "an alcohol" and "an L-1-phosphatidyl glycerol." Improvements in the handling of generic reactions include display of such reactions on compound pages.

Improvements to Desktop BioCyc

This section describes improvements to the version of BioCyc that runs locally on your desktop computer in conjunction with the Pathway Tools (PTools) software.

• FBA Module Supports Gene Knock-Outs: The PTools FBA module has been extended to support prediction of growth or no-growth for single and double gene and/or reaction knock-outs. See the FBA chapter of the User's Guide for more details. This module predicts growth/no-growth for E. coli using EcoCyc with an accuracy of 86.1%.

• 64-bit Microsoft Windows Now Supported; 32-bit Windows No Longer Supported: This and future releases of Pathway Tools will support the Windows 64-bit platform; the Windows 32-bit platform will no longer be supported because memory layout issues were preventing the software from working reliably on the 32-bit platform. Operation under Windows-7 has also been improved in several respects. Please be aware of the following current limitations of the 64-bit Windows version:
  • In this version 15.5, Pathway Tools web server mode does not currently work for Windows-64. We hope to have this problem fixed for the next release or sooner.

• Growth Medium Search: The new command Tools → Search → Growth Media enables searching for growth media in the current PGDB according to several criteria.

• Improvements to Generic Reactions: Generic reactions in PGDBs are reactions whose classes are substrates, such as "an alcohol" and "an L-1-phosphatidyl glycerol." Improvements in the handling of generic reactions include display of such reactions on compound pages.

For more details and examples see:

• Pathway Tools release notes
• EcoCyc release notes
• MetaCyc release notes

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