Fig. 1.

Intermediates in bile acid biosynthesis pathways. (A) Formation of dihydroxy-3-oxocholest-4-en-26-oic acids from cholesterol via the acidic, neutral and 25-hydroxylase pathways [1,2]. In the acidic and neutral pathway stereochemistry at C-25 is assumed to be 25 R unless otherwise indicated. (B) Formation of (25 R)CA⁴-7α,24 S-diol-3-one and (25 S)CA⁴-7α,24 S-diol-3-one via the 24 S-hydroxylase pathway (red box) [21] and of 25 S- and 25 R-epimers of CA⁴-7α,12α-diol-3-one in the absence of CYP27A1 [26] (gold box). For simplicity the formation and hydrolysis of CoA-thioesters in the steps preceding and succeeding C-25 racemisation are not shown. (C) Latter steps of the acidic pathway proceeding mostly in the peroxisome leading to the four diastereomers of CA⁴-7α,24-diol-3-one. In liver the dominant product is (25 R)CA⁴-7α,24 R-diol-3-one. The inset shows the formation of (25 S)CA⁴-7α,24 R-diol-3-one from its CoA-thioester following C-25 racemisation. In CTX the enzyme CYP27A1 is deficient, while in SPG5 CYP7B1 is deficient. Abbreviations: ACOX2: acyl-coenzyme A oxidase 2. AMACR: α-methylacyl-CoA racemase. BACS: bile acid-CoA synthetase. C: Cholestane. CA: Cholestanoic acid. CH25H: Cholesterol 25-hydroxylase. CYP: Cytochrome P450. DBP: D-Bifunctional Protein. HSD3B7: 3β-Hydroxysteroid dehydrogenase type 7. LBP: L-Bifunctional protein. SPCx: Sterol carrier protein x. VLCS: Very long chain Co-A synthetase. The dihydroxy-3-oxocholest-4-en-26-oic acids CA⁴-7α,25-diol-3-one, CA⁴-7α,12α-diol-3-one and CA⁴-7α,24-diol-3-one are colour coded green, gold and red, respectively.