7alpha-dehydroxylation of cholic acid and chenodeoxycholic acid by bai operon genes (Mus musculus)

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This pathway summarizes the gut bacterial 7α dehydroxylation of unconjugated primary bile acids, in which deconjugated cholic acid (CA) and chenodeoxycholic acid (CDCA) are converted to the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, by Firmicutes such as Clostridium and related genera that carry bile acid–inducible (bai) genes.

It follows a multi-step bai operon–dependent route in which bile acids are transported into the cell and transformed through CoA thioester formation, sequential oxidations, a 7α dehydration step and subsequent reductions and CoA removal, highlighting the central roles of BaiB, BaiA2, BaiCD, BaiE, BaiF, BaiH and BaiN. Because no single consensus mechanism is fully established, the pathway explicitly shows the two main proposed enzyme orders derived from recent in vitro and in vivo work. The model highlighted in green, emphasizes an oxidative–reductive sequence in which BaiH catalyses the first reductive step, while BaiCD and BaiA2 act twice, at the beginning and the end of the redox cascade:

BaiB → BaiA2 → BaiCD → BaiE → BaiF → BaiH → BaiCD → BaiA2

An alternative model (highlighted in purple) supported by other reconstitution and review studies, proposes the sequence:

BaiB → BaiA2 → BaiCD → BaiF → BaiE → BaiN → BaiN → BaiA2

In addition, downstream of LCA formation, the diagram shows, highlighted in light blue, microbiota derived LCA by-products such as 3 oxoLCA, isoLCA, 3 oxoalloLCA, alloLCA and isoalloLCA, which are now established in human stool and are produced by combinations of bai encoded enzymes together with additional 5α/5β reductases and 3α/3β HSDHs encoded in distinct gene clusters; for these branches, the overall existence of the metabolites and enzyme activities is well supported, whereas the exact sequence of intermediates remains partially reconstructed.

The diagram therefore captures the shared intermediates and directionality of 7α dehydroxylation, while indicating that the exact order and division of labor among bai and non bai enzymes, and their strain specific variants, remain active areas of research.

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>> Metabolite and enzyme abbreviations used with their full common names:

• CA: Cholic acid

• CA-CoA: Cholyl-coenzyme A

• 3-oxoCA-CoA: 3-oxo-Cholic acid-coenzyme A

• 3-oxoΔ4-CA-CoA: 3-oxo-delta4-cholyl-coenzyme A

• 3-oxoΔ4-CA: 3-oxo-delta4-Cholic acid

• 3-oxoΔ4,6-DCA: 3-oxo-delta4,6-Deoxycholic acid

• 3-oxoΔ4-DCA: 3-oxo-delta4-Deoxycholic acid

• 3-oxoDCA: 3-oxo-Deoxycholic acid

• DCA: Deoxycholic acid

• IsoDCA: Isodeoxycholic acid

• CDCA: Chenodeoxycholic Acid

• CDCA-CoA: Chenodeoxycholoyl-coenzyme A

• 3-oxoCDCA-CoA: 3-oxo-chenodeoxycholyl-coenzyme A

• 3-oxoΔ4-CDCA-CoA: 3-Oxo-delta4-chenodeoxycholyl-coenzyme A

• 3-oxoΔ4-CDCA: 3-Oxo-4-cholenoic acid

• 3-oxoΔ4,6-LCA: 3-Oxo-4,6-choladienoic acid

• 3-oxoΔ4-LCA: 3-Oxo-4-cholenic acid

• 3-oxoLCA: Dehydrolithocholic Acid

• LCA: Lithocholic acid

• IsoLCA: Isolithocholic acid

• 3-oxoalloLCA: 3-Oxoallolithocholic acid

• isoalloLCA: Isoallolithocholic acid

• alloLCA: Allolithocholic acid

• BAIB_CLOSV: Bile acid-coenzyme A ligase, Clostridium scindens

• BAIA1_CLOSV: 3alpha-hydroxy bile acid-coenzyme A-ester 3-dehydrogenase, Clostridium scindens

• BAICD_CLOSV: 3-oxocholoyl-coenzyme A 4-desaturase, Clostridium scindens

• BAIF_CLOSV: Bile acid coenzyme A-transferase BaiF, Clostridium scindens

• BAIE_CLOSV: Bile acid 7alpha-dehydratase, Clostridium scindens

• BAIN_CLOS5: 3-dehydro-bile acid delta(4,6)-reductase, Clostridium scindens

• BAIA2_CLOSV: 3alpha-hydroxy bile acid-coenzyme A-ester 3-dehydrogenase 2, Clostridium scindens

• BAIH_CLOSV: 7-beta-hydroxy-3-oxochol-24-oyl-coenzyme A 4-desaturase, Clostridium scindens

• 3AHDP_MEDG7: 3alpha-hydroxysteroid dehydrogenase, Mediterraneibacter gnavus

• 3AHD_EGGLE: 3alpha-hydroxysteroid dehydrogenase, Eggerthella lenta

• 3BHDP_MEDG7: 3beta-hydroxysteroid dehydrogenase, Mediterraneibacter gnavus

• 3BHD2_EGGLE: 3beta-hydroxysteroid dehydrogenase 2, Eggerthella lenta

• 5AR: 5alpha-reductase