Database Authors
Pallavi Subhraveti1, Quang Ong1, Ingrid Keseler1, Dan Weaver1, Tim Holland1, Anamika Kothari1, Ron Caspi1, Peter D Karp1, Amanda Mackie2, David S. Weiss3
1SRI International, 2Macquarie University, 3University of Iowa
Summary Clostridioides difficile was discovered in 1935 [Hall35], but was not recognized as a pathogen until the late 1970s [Bartlett78]. Starting at the turn of the 21st century, it became recognized as the causative agent for an emerging number of nosocomial and community-acquired infections with symptoms ranging from mild diarrhea to pseudomembranous colitis and toxic megacolon [Bartlett06, Rupnik09, Knight15, Lessa15].

The organism is strictly anaerobic and has a unique metabolism, using multiple Stickland-type amino acid fermentation reactions coupled to Rnf complex-mediated sodium/proton gradient formation for ATP generation. It also produces a number of straight-chain organic acids including acetate, lactate, propanoate and butanoate. The organism uses pyruvate formate-lyase as a central enzyme in its sugar catabolism, and has an incomplete tricarboxylic acid cycle to prevent unnecessary NADH formation. There is no quinone-based electron transfer chain. Rather, electrons derived from NADH are bifurcated to two different electron acceptors, an enoyl-CoA and ferredoxin. The free energy resulting from redox potential difference between ferredoxin and NAD+ is used to transport ions across the membrane, generating a proton motive force that is used for ATP generation [NeumannSchaal19].

The symptoms of Clostridioides difficile infections, including severe intestinal damage, are believed to be mainly caused by the two large clostridial toxins A (tcdA) and B (tcdB) [Carter10].

This Pathway/Genome Database (PGDB) for Clostridioides difficile 630 was created on Aug 10, 2014 using version 18.5 of the PathoLogic component of the Pathway Tools software [Karp11, Karp19] and the MetaCyc reference database [Caspi20] from the annotated genome [Sebaihia06, Monot11] as obtained from RefSeq on May 21, 2014. The database was later updated with revised genome annotation using RefSeq files downloaded on Dec 15, 2014 as well as MicroScope annotation downloaded on Jan 14, 2015.

The PGDB, which integrates the biochemical reaction network and metabolic pathways of the organism with its genome, was improved by limited manual curation. Gene Ontology terms were added by manual curation and from a UniProt file downloaded on July 15, 2015. The curation of multiple enzymes involved in peptidoglycan synthesis was undertaken during 2020 with expert advice from David S. Weiss from the University of Iowa.

Development of this PGDB was supported by BioCyc subscription revenues and by grant GM080746 from the National Institute of Health.

Genome
RepliconTotal GenesProtein GenesRNA GenesPseudogenesSize (bp)NCBI Link
chromosome4,2183,796406164,290,252RefSeq:NC_009089
plasmid pCD6301010007,881RefSeq:NC_008226
Total:4,2283,806406164,298,133
Ortholog data available?Yes
Database Contents
Genes4,228
Pathways257
Enzymatic Reactions1,140
Transport Reactions50
Polypeptides3,814
Protein Complexes103
Enzymes825
Transporters445
Compounds1,006
Transcription Units2,397
tRNAs87
Growth Media20
Transcriptional Regulation54
Protein Features6,054
GO Terms29,456
Database Version29.0
Synonyms Clostridioides difficile 630
Clostridium difficile 630 (epidemic type X)
Clostridium difficile str. 630
Clostridium difficile strain 630
Clostridium difficile 630
Taxonomic Lineage cellular organisms
Bacteria <bacteria>
Terrabacteria group
Bacillota
Clostridia
Peptostreptococcales
Peptostreptococcaceae
Clostridioides
Clostridioides difficile
Clostridioides difficile 630
Genetic Code Number 11 -- Bacterial, Archaeal and Plant Plastid (same as Standard, except for alternate initiation codons)
GOLD0000306
NCBI BioProjectPRJNA57679
NCBI-Taxonomy272563
Relationship to Oxygenanaerobe
NCBI Genome Typereference

References

Bartlett06: Bartlett JG (2006). "Narrative review: the new epidemic of Clostridium difficile-associated enteric disease." Ann Intern Med 145(10);758-64. PMID: 17116920

Bartlett78: Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB (1978). "Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia." N Engl J Med 298(10);531-4. PMID: 625309

Carter10: Carter GP, Rood JI, Lyras D (2010). "The role of toxin A and toxin B in Clostridium difficile-associated disease: Past and present perspectives." Gut Microbes 1(1);58-64. PMID: 20664812

Caspi20: Caspi R, Billington R, Keseler IM, Kothari A, Krummenacker M, Midford PE, Ong WK, Paley S, Subhraveti P, Karp PD (2020). "The MetaCyc database of metabolic pathways and enzymes - a 2019 update." Nucleic Acids Res 48(D1);D445-D453. PMID: 31586394

Hall35: Hall IC, OToole E. (1935). "Intestinal flora in new-born infants: with a description of a new pathogenic anaerobe, Bacillus difficilis." American Journal of Diseases of Children 49(2);390.

Karp11: Karp PD, Latendresse M, Caspi R (2011). "The pathway tools pathway prediction algorithm." Stand Genomic Sci 5(3);424-9. PMID: 22675592

Karp19: Karp PD, Midford PE, Billington R, Kothari A, Krummenacker M, Latendresse M, Ong WK, Subhraveti P, Caspi R, Fulcher C, Keseler IM, Paley SM (2019). "Pathway Tools version 23.0 update: software for pathway/genome informatics and systems biology." Brief Bioinform. PMID: 31813964

Knight15: Knight DR, Elliott B, Chang BJ, Perkins TT, Riley TV (2015). "Diversity and Evolution in the Genome of Clostridium difficile." Clin Microbiol Rev 28(3);721-41. PMID: 26085550

Lessa15: Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC, Wilson LE, Winston LG, Cohen JA, Limbago BM, Fridkin SK, Gerding DN, McDonald LC (2015). "Burden of Clostridium difficile infection in the United States." N Engl J Med 372(9);825-34. PMID: 25714160

Monot11: Monot M, Boursaux-Eude C, Thibonnier M, Vallenet D, Moszer I, Medigue C, Martin-Verstraete I, Dupuy B (2011). "Reannotation of the genome sequence of Clostridium difficile strain 630." J Med Microbiol 60(Pt 8);1193-9. PMID: 21349987

NeumannSchaal19: Neumann-Schaal M, Jahn D, Schmidt-Hohagen K (2019). "Metabolism the Difficile Way: The Key to the Success of the Pathogen Clostridioides difficile." Front Microbiol 10;219. PMID: 30828322

Rupnik09: Rupnik M, Wilcox MH, Gerding DN (2009). "Clostridium difficile infection: new developments in epidemiology and pathogenesis." Nat Rev Microbiol 7(7);526-36. PMID: 19528959

Sebaihia06: Sebaihia M, Wren BW, Mullany P, Fairweather NF, Minton N, Stabler R, Thomson NR, Roberts AP, Cerdeno-Tarraga AM, Wang H, Holden MT, Wright A, Churcher C, Quail MA, Baker S, Bason N, Brooks K, Chillingworth T, Cronin A, Davis P, Dowd L, Fraser A, Feltwell T, Hance Z, Holroyd S, Jagels K, Moule S, Mungall K, Price C, Rabbinowitsch E, Sharp S, Simmonds M, Stevens K, Unwin L, Whithead S, Dupuy B, Dougan G, Barrell B, Parkhill J (2006). "The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome." Nat Genet 38(7);779-86. PMID: 16804543

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