The BioCyc collection of microbial genomes and metabolic pathways

Karp, Peter D.; Billington, Richard; Caspi, Ron; Fulcher, Carol A.; Latendresse, Mario; Kothari, Anamika; Keseler, Ingrid M.; Krummenacker, Markus; Midford, Peter E.; Ong, Quang; Ong, Wai Kit; Paley, Suzanne M.; Subhraveti, Pallavi

doi:10.1093/bib/bbx085

Cited by 619 publications

(454 citation statements)

References 20 publications

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“…EV is wild type with pAH9 (EBT169) and GFP is wild type with pAH13 (UM20). Streptavidin IR680LT was used to detect HD73_4231 (PycA homolog) which served as a loading control (63, 64). The color blot showing both anti-GFP and Streptavidin on a single gel is Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of the Extracytoplasmic Function σ factor σ^Pby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP

Nauta

Müh

et al. 2019

Preprint

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30Bacteria can utilize alternative σ factors to regulate sets of genes in response to 31 changes in the environment. The largest and most diverse group of alternative σ factors are the 32 Extracytoplasmic Function (ECF) σ factors. σ P is an ECF σ factor found in Bacillus anthracis, B. 33 cereus, and B. thuringiensis. Previous work showed σ P is induced by ampicillin, a β-lactam 34 antibiotic, and required for resistance to ampicillin. However, it was not known how activation of 35 σ P is controlled or what other antibiotics may activate σ P . Here we report that activation of σ P is 36 specific to a subset of β-lactams and σ P is required for resistance to these β-lactams. We 37 demonstrate that activation of σ P is controlled by the proteolytic destruction of the anti-σ factor, 38RsiP, and that degradation of RsiP requires multiple proteases. Upon exposure to β-lactams, 39 the extracellular domain of RsiP is cleaved by an unknown protease, which we predict cleaves 40 at site-1. Following cleavage by the unknown protease, the N-terminus of RsiP is further 41 degraded by the site-2 intramembrane protease, RasP. Our data indicate that RasP cleavage of 42RsiP is not the rate-limiting step in σ P activation. This proteolytic cascade leads to activation of 43 σ P which induces resistance to β-lactams likely via increased expression of β-lactamases. 44 45 Importance 46

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Section: Resultsmentioning

confidence: 99%

Activation of the Extracytoplasmic Function σ factor σ^Pby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP

Nauta

Müh

et al. 2019

Preprint

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“…Subsequent to merging the existing S. coelicolor GEMs, we performed a number of further curations of the model: including improvement of annotations, both in terms of coverage and number of different databases, e.g. KEGG (Kanehisa, 2000;Kanehisa et al, 2019), BioCyC (Karp et al, 2017), ChEBI (Hastings et al, 2016) and MetaNetX (Moretti et al, 2016). All reactions and metabolites have been given identifiers according to the BiGG namespace (King et al, 2016), and all reactions are categorized into 15 different subsystems, covering 128 different pathways.…”

Section: Reproducible Reconstruction Of Sco-gemmentioning

confidence: 99%

Enzyme-constrained models and omics analysis of Streptomyces coelicolor reveal metabolic changes that enhance heterologous production

Sulheim

Kumelj

Dissel

et al. 2019

Preprint

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Streptomyces coelicolor M1152 is a widely used host strain for the heterologous production of novel small molecule natural products, genetically engineered for this purpose through e.g. deletion of four of its native biosynthetic gene clusters (BGCs) for improved precursor supply. Regardless of its potential, a systems understanding of its tight regulatory network and the effects of the significant genomic changes in M1152 is missing. In this study, we compare M1152 to its ancestor M145, thereby connecting observed phenotypic differences to changes on transcription and translation. Measured protein levels are connected to predicted metabolic fluxes, facilitated by an enzyme-constrained genome-scale model (GEM), that by itself is a consensus result of a community effort. This approach connects observed differences in growth rate and glucose consumption to changes in central carbon metabolism, accompanied by differential expression of important regulons. Results suggest that precursors supply is not limiting secondary metabolism, informing that alternative strategies will be beneficial for further development of S. coelicolor for heterologous production of novel compounds.

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“…Illustrating a more serious error, a 2013 paper claimed that Rv1749c is part of a VapBC toxin-antitoxin system in M. bovis 125 , but their cited source 126 mentioned Rv1749c neither in the paper nor in the supplementary material. The same paper claims Rv0988 is a hydrolase, but provides no citation for this claim 125 , and no major database supports this claim 2,5,17,[34][35][36]38 . These examples underscore the need for skepticism and caution when evaluating evidence for functional annotation in literature.…”

Section: Manual Annotationmentioning

confidence: 99%

“…To assess the novelty of manual product annotations, we compared each to their counterparts on UniProt 17 , Mtb Network Portal 5 (which included annotations from TBDB 1 ), PATRIC 2 , RefSeq 34 , BioCyc 35 , and KEGG 36 . We obtained the UniProt, Mtb Network Portal, and RefSeq annotations for each of our genes with new product annotation programmatically.…”

Section: Comparison To Existing Databasesmentioning

confidence: 99%

Structure-aware M. tuberculosis functional annotation uncloaks resistance, metabolic, and virulence genes

Modlin

Gunasekaran

et al. 2018

Preprint

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Each decade, billions are invested in Tuberculosis (TB) research to further characterize M. tuberculosis pathogenesis. Despite this investment, nearly half of the 4,031 M. tuberculosis protein-coding genes lack descriptive annotation in community databases, due largely to incomplete reconciliation with the literature and a lack of structure-based methods for functional inference. We coin the term "hypotheticome" as the set of genes in an organism without known function. For M. tuberculosis' hypotheticome, we compiled the set of genes lacking functional assignment in the most frequently used Mycobacteria annotation database through systematic, exhaustive manual literature curation and 3Dprotein structure-based inference, and reconciled these annotations with frequented functional databases, creating a comprehensive M. tuberculosis functional knowledge-base. In doing so, we also introduce standard usage of qualifying adjectives based on quantitative measures of certainty with the hope that this approach is adopted in choosing qualifiers for future functional assignments.Through these methods we functionally annotated 41.3% of the M. tuberculosis hypotheticome, and provide insight into its pathogenesis, antibiotic-resistance, and virulence. Processes implicated in the unique lifestyle of M. tuberculosis of long-term persistence and obligate pathogenesis in genotoxic host microenvironmentslipid metabolism, polyketide biosynthesis, and membrane transport and effluxwere overrepresented in our annotation. Our structural similarity approach unturned proteins that appear critical in host-interaction through apparent host mimicry, particularly involving the phagosome and vesicle-mediated transport, as well as putative structural analogs for highly mutable protein classes, including dozens of PE/PPE family proteins which are major players at the host-pathogen interface, and sixteen potential efflux pumps which are integral to M. tuberculosis drug tolerance. Hypotheses drawn from these proteins' function may help characterize the onset of latency and identify therapeutic targets. A unified annotation is essential for clear communication about M. tuberculosis. These improvements provide the most comprehensive M. tuberculosis genome annotation to date, and the approach presented can be applied to systematically annotate the genome of other organisms. We provide our novel annotations in General Feature Format with Enzyme Commission and Gene Ontology terms for integration into existing annotation frameworks.

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The BioCyc collection of microbial genomes and metabolic pathways

Cited by 619 publications

References 20 publications

Activation of the Extracytoplasmic Function σ factor σ^Pby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP

Activation of the Extracytoplasmic Function σ factor σ^Pby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP

Enzyme-constrained models and omics analysis of Streptomyces coelicolor reveal metabolic changes that enhance heterologous production

Structure-aware M. tuberculosis functional annotation uncloaks resistance, metabolic, and virulence genes

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The BioCyc collection of microbial genomes and metabolic pathways

Cited by 619 publications

References 20 publications

Activation of the Extracytoplasmic Function σ factor σPby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP

Activation of the Extracytoplasmic Function σ factor σPby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP

Enzyme-constrained models and omics analysis of Streptomyces coelicolor reveal metabolic changes that enhance heterologous production

Structure-aware M. tuberculosis functional annotation uncloaks resistance, metabolic, and virulence genes

Contact Info

Product

Resources

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Activation of the Extracytoplasmic Function σ factor σ^Pby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP

Activation of the Extracytoplasmic Function σ factor σ^Pby β-lactams inBacillus thuringiensisrequires the site-2 protease RasP