Bile acid synthesis II — side-chain oxidation, peroxisomal shortening and amino-acid conjugation; CYP27A1/AMACR/ACOX2/SLC27A5/BAAT

After the sterol nucleus of cholesterol has been hydroxylated (the ring-modification segment: CYP7A1/CYP7B1/HSD3B7/AKR1D1), the C27 side chain must be oxidised and shortened by three carbons to give the mature C24 bile acids, which are then conjugated to an amino acid before secretion. Mitochondrial sterol 27-hydroxylase (CYP27A1) initiates side-chain oxidation, hydroxylating C27 of the 5beta-cholestane-3alpha,7alpha,12alpha-triol (and the 7alpha-hydroxy-diol) and further oxidising it to the C27 bile-acid intermediates 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid (THCA) and its 12-deoxy congener DHCA. These C27 acids are activated to their CoA thioesters and imported into the peroxisome, where alpha-methylacyl-CoA racemase (AMACR) converts the (25R) diastereomer to the (25S) form required for beta-oxidation, and the peroxisomal branched-chain acyl-CoA oxidase ACOX2 catalyses the first (oxidase) step of one round of beta-oxidation; the downstream MFP2/SCPx steps release propionyl-CoA to give the C24 bile-acyl-CoAs choloyl-CoA and chenodeoxychenoyl-CoA. Bile acid-CoA:amino acid N-acyltransferase (BAAT) then transfers the C24 bile acid from CoA onto glycine or taurine, forming the glyco- and tauro-conjugated bile salts that are the major biliary species; the ER-membrane bile acyl-CoA synthetase SLC27A5 (cholate-CoA ligase / FATP5) re-activates free bile acids to their CoA esters, chiefly in the enterohepatic recycling loop, feeding BAAT for re-conjugation. Inherited defects across this segment cause cerebrotendinous xanthomatosis (CYP27A1), AMACR deficiency (an adult sensorimotor neuropathy with bile-acid abnormalities), ACOX2 deficiency (a bile-acid synthesis defect with liver disease/dystonia) and familial hypercholanemia / bile acid conjugation defect (BAAT).