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MetaCyc Pathway: cholate degradation (bacteria, anaerobic)

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: 7α-dehydroxylation pathway, bile acid degradation, cholate degradation, bile acid 7α-dehydroxylation pathway

Superclasses: Degradation/Utilization/Assimilation Degradation/Utilization/Assimilation - Other

Some taxa known to possess this pathway include ? : Clostridium scindens VPI 12708 Inferred from experiment [Dawson96], Clostridium sp. TO-931 Inferred from experiment [Wells00], [Clostridium] hylemonae DSM 15053 Inferred from experiment [Ridlon10], [Clostridium] scindens ATCC 35704 Inferred from experiment [Ridlon12]

Expected Taxonomic Range: Bacteria

Summary:
General Background

In the human large intestine a small proportion of unconjugated, primary bile acids that escape reabsorption in the small intestine are metabolized by bacteria to secondary bile acids. For example cholate is metabolized to deoxycholate as shown in this pathway. Similarly, chenodeoxycholate is metabolized to lithocholate. Secondary bile acids can enter the bile acid pool and in some individuals they can accumulate to relatively high levels and may contribute to the pathogenesis of gastrointestinal diseases.

The 7α-dehydroxylation pathway that converts primary bile acids into secondary bile acids has been found in only some species of anaerobic intestinal clostridia. These organisms contain the bile acid-inducible (bai) operons and genes that comprise the bai regulon. Inducers of gene expression include primary 5β bile acids such as cholate and the primary 5α bile acid allocholate [Ridlon10]. Gene products involved in the pathway may vary depending upon the bile acid substrate. For example, the products of genes baiH and baiI may be involved in degradation of the minor 7β-hydroxy bile acid ursodeoxycholate (reviewed in [Ridlon06]). More widespread, constitutive reactions of bile acid metabolism by intestinal bacteria are shown in pathway glycocholate metabolism (bacteria).

Clostridium scindens VPI 12708 (previously named Eubacterium sp. strain VPI 12708), a human intestinal isolate, employs a novel, multi-step pathway for bile acid 7α-dehydroxylation. The use of bile acids as electron acceptors for fermentative metabolism provides an important niche for 7α-dehydroxylating bacteria in the human colon. It is predicted to provide energy due to a net 2-electron reduction. Energy could be conserved if the product of gene baiF can transfer coenzyme A via a proposed ATP-independent transferase activity. Removal of toxic secondary bile acids from the microenvironment would also be necessary. In [Ridlon10] and reviewed in [Ridlon06].

About This Pathway

The currently proposed bile acid 7α-dehydroxylation pathway is shown here, although further characterization is necessary [Ridlon12].

In Clostridium scindens VPI 12708 the oxidative part of the pathway begins with active transport of a bile acid across the bacterial membrane into the cell by the product of gene baiG, a H+-dependent primary bile acid transporter [Mallonee96]. The bile acid is activated by ligation to coenzyme A in an ATP-dependent manner by the product of baiB. The 3α-hydroxy group of the bile acid-CoA thioester is oxidized by the isozyme products of the three genes baiA1, baiA2 and baiA3 that can utilize NAD+ or NADP+ and are specific for bile acid-CoA conjugates. A double bond is inserted between C-4 and C-5 by the product of baiCD, an NAD+-dependent flavoprotein.

After the rate-limiting and irreversible 7α-hydroxy dehydration by the product of gene baiE, the 3-oxo-Δ4,6-intermediate is sequentially reduced in three reactions. The genes encoding the reductase(s) have not yet been identified.

It is not known precisely when in the pathway coenzyme A is removed from the bile acid by the product of gene baiF (in [Ye99]. It was suggested occur by ester hydrolysis, or by transfer to incoming bile acids (in [Kang08]). Subsequent work showed BaiF to have bile acid coenzyme A transferase activity [Ridlon12]. BaiF is shown here as catalyzing the last reaction in the pathway, as in [Dawson96, Ridlon12]. The resulting 7α-dehydroxylated bile acid is then hypothesized to be transported out of the bacterial cell by an as yet unidentified transporter. Reviewed in [Hylemon98, Ridlon06].

In addition, a baiJKL operon has been identified in Clostridium scindens VPI 12708 and [Clostridium] hylemonae DSM 15053, but it appears to be absent in [Clostridium] scindens ATCC 35704. Gene baiK in Clostridium scindens VPI 12708 was shown to also encode a bile acid coenzyme A transferase, although its physiological function remains to be determined [Ridlon12].

Credits:
Revised 03-Jun-2010 by Fulcher CA , SRI International
Revised 07-Mar-2014 by Fulcher CA , SRI International


References

Dawson96: Dawson JA, Mallonee DH, Bjorkhem I, Hylemon PB (1996). "Expression and characterization of a C24 bile acid 7 alpha-dehydratase from Eubacterium sp. strain VPI 12708 in Escherichia coli." J Lipid Res 1996;37(6);1258-67. PMID: 8808760

Hylemon98: Hylemon PB, Harder J (1998). "Biotransformation of monoterpenes, bile acids, and other isoprenoids in anaerobic ecosystems." FEMS Microbiol Rev 1998;22(5);475-88. PMID: 9990726

Kang08: Kang DJ, Ridlon JM, Moore DR, Barnes S, Hylemon PB (2008). "Clostridium scindens baiCD and baiH genes encode stereo-specific 7alpha/7beta-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductases." Biochim Biophys Acta 1781(1-2);16-25. PMID: 18047844

Mallonee96: Mallonee DH, Hylemon PB (1996). "Sequencing and expression of a gene encoding a bile acid transporter from Eubacterium sp. strain VPI 12708." J Bacteriol 178(24);7053-8. PMID: 8955384

Ridlon06: Ridlon JM, Kang DJ, Hylemon PB (2006). "Bile salt biotransformations by human intestinal bacteria." J Lipid Res 47(2);241-59. PMID: 16299351

Ridlon10: Ridlon JM, Kang DJ, Hylemon PB (2010). "Isolation and characterization of a bile acid inducible 7alpha-dehydroxylating operon in Clostridium hylemonae TN271." Anaerobe 16(2);137-46. PMID: 19464381

Ridlon12: Ridlon JM, Hylemon PB (2012). "Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium." J Lipid Res 53(1);66-76. PMID: 22021638

Wells00: Wells JE, Hylemon PB (2000). "Identification and characterization of a bile acid 7alpha-dehydroxylation operon in Clostridium sp. strain TO-931, a highly active 7alpha-dehydroxylating strain isolated from human feces." Appl Environ Microbiol 66(3);1107-13. PMID: 10698778

Ye99: Ye HQ, Mallonee DH, Wells JE, Bjorkhem I, Hylemon PB (1999). "The bile acid-inducible baiF gene from Eubacterium sp. strain VPI 12708 encodes a bile acid-coenzyme A hydrolase." J Lipid Res 1999;40(1);17-23. PMID: 9869646

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Coleman88: Coleman JP, White WB, Lijewski M, Hylemon PB (1988). "Nucleotide sequence and regulation of a gene involved in bile acid 7-dehydroxylation by Eubacterium sp. strain VPI 12708." J Bacteriol 170(5);2070-7. PMID: 2834320

GopalSrivastava90: Gopal-Srivastava R, Mallonee DH, White WB, Hylemon PB (1990). "Multiple copies of a bile acid-inducible gene in Eubacterium sp. strain VPI 12708." J Bacteriol 172(8);4420-6. PMID: 2376563

Hylemon91: Hylemon PB, Melone PD, Franklund CV, Lund E, Bjorkhem I (1991). "Mechanism of intestinal 7 alpha-dehydroxylation of cholic acid: evidence that allo-deoxycholic acid is an inducible side-product." J Lipid Res 32(1);89-96. PMID: 2010697

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Mallonee90: Mallonee DH, White WB, Hylemon PB (1990). "Cloning and sequencing of a bile acid-inducible operon from Eubacterium sp. strain VPI 12708." J Bacteriol 172(12);7011-9. PMID: 2254270

Mallonee92: Mallonee DH, Adams JL, Hylemon PB (1992). "The bile acid-inducible baiB gene from Eubacterium sp. strain VPI 12708 encodes a bile acid-coenzyme A ligase." J Bacteriol 1992;174(7);2065-71. PMID: 1551828

Mallonee95: Mallonee DH, Lijewski MA, Hylemon PB (1995). "Expression in Escherichia coli and characterization of a bile acid-inducible 3 alpha-hydroxysteroid dehydrogenase from Eubacterium sp. strain VPI 12708." Curr Microbiol 1995;30(5);259-63. PMID: 7766153

Rubio06: Rubio S, Larson TR, Gonzalez-Guzman M, Alejandro S, Graham IA, Serrano R, Rodriguez PL (2006). "An Arabidopsis mutant impaired in coenzyme A biosynthesis is sugar dependent for seedling establishment." Plant Physiol 140(3);830-43. PMID: 16415216

White81: White BA, Cacciapuoti AF, Fricke RJ, Whitehead TR, Mosbach EH, Hylemon PB (1981). "Cofactor requiremets for 7 alpha-dehydroxylation of cholic and chenodeoxycholic acid in cell extracts of the intestinal anaerobic bacterium, Eubacterium species V.P.I. 13708." J Lipid Res 22(6);891-8. PMID: 7276750

White88a: White WB, Franklund CV, Coleman JP, Hylemon PB (1988). "Evidence for a multigene family involved in bile acid 7-dehydroxylation in Eubacterium sp. strain VPI 12708." J Bacteriol 170(10);4555-61. PMID: 3170477

White88b: White WB, Coleman JP, Hylemon PB (1988). "Molecular cloning of a gene encoding a 45,000-dalton polypeptide associated with bile acid 7-dehydroxylation in Eubacterium sp. strain VPI 12708." J Bacteriol 170(2);611-6. PMID: 2448288


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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Thu Nov 20, 2014, BIOCYC14A.