Alternative (acidic) bile acid biosynthesis pathway (Homo sapiens)

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This pathway depicts the alternative, or acidic, route of primary bile acid synthesis, in which cholesterol is first hydroxylated on the side chain (C24, C25 or C26) by enzymes such as CYP46A1, CH25H or CYP27A1 to form regulatory oxysterols that are then 7α hydroxylated and further oxidized to 7α,24/25/26 dihydroxy 4 cholesten 3 one. From this common intermediate, 12α hydroxylation by CYP8B1 can drive formation of cholic acid (CA), whereas bypassing CYP8B1 favours chenodeoxycholic acid (CDCA), with downstream ring reduction and side chain shortening steps (involving HSD3B7, AKR1D1, AKR1C4, CYP27A1 and peroxisomal β oxidation enzymes) converging with the classical pathway from one side at 3α,7α-dihydroxy-5β-cholestan-26-al and related intermediates to yield CDCA, and from the other side at 3α,7α,12α-trihydroxy-5β-cholestan-26-al and related intermediates to yield CA.

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

• Cholesterol: Cholesterol

• ST 27:1;O2: Cerebrosterol

• ST 27:1;(24)O3: 7alpha,24-dihydroxycholesterol

• ST 27:1;(25)O2: 25-hydroxy-cholesterol

• ST 27:1;(25)O3: 7alpha,25-dihydroxycholesterol

• ST 27:1;(27)O3: 7alpha,27-dihydroxycholesterol

• ST 27:1;(27)O2: 27-hydroxy-cholesterol

• ST 27:2;O3: Cholestenoic acid

• ST 27:2;O4: 3beta,7alpha-Dihydroxy-5-cholestenoic acid

• ST 27:3;O4: 7alpha-hydroxy-3-oxocholest-4-en-27-oic acid

• ST 27:2;(24)O3: 7alpha,24-dihydroxycholest-4-en-3-one

• ST 27:2;(25)O3: 7alpha,25-dihydroxycholest-4-en-3-one

• ST 27:2;(26)O3: 7alpha,26-dihydroxycholest-4-en-3-one

• ST 27:2;(24)O4: 7alpha,12alpha,24-trihydroxycholest-4-en-3-one

• ST 27:2;(25)O4: 7alpha,12alpha,25-trihydroxycholest-4-en-3-one

• ST 27:2;(26)O4: 7alpha,12alpha,26-trihydroxycholest-4-en-3-one

• ST 27:1;(24)O4: 7alpha,12alpha,24-trihydroxy-5beta-cholestan-3-one

• ST 27:1;(25)O4: 7alpha,12alpha,25-trihydroxy-5beta-cholestan-3-one

• ST 27:1;(26)O4: 7alpha,12alpha,26-trihydroxy-5beta-cholestan-3-one

• ST 27:0;(24)O4: 5beta-Cholestane-3alpha,7alpha,12alpha,24-tetrol

• ST 27:0;(25)O4: 5beta-Cholestane-3alpha,7alpha,12alpha,25-tetrol

• ST 27:0;(26)O4: 5beta-Cholestane-3alpha,7alpha,12alpha,26-tetrol

• ST 27:1;O4: 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-al

• CA: Cholic acid

• ST 27:1;(24)O3: 7alpha,24-dihydroxy-5beta-cholestan-3-one

• ST 27:1;(25)O3: 7alpha,25-dihydroxy-5beta-cholestan-3-one

• ST 27:1;(26)O3: 7alpha,26-dihydroxy-5beta-cholestan-3-one

• ST 27:0;(24)O3: 5beta-cholestane-3alpha,7alpha,24-triol

• ST 27:0;(25)O3: 5beta-cholestane-3alpha,7alpha,25-triol

• ST 27:0;(26)O3: 5beta-cholestane-3alpha,7alpha,26-triol

• ST 27:1;O3: 3alpha,7alpha-dihydroxy-5beta-cholestan-26-al

• CDCA: Chenodeoxycholic acid

• CYP39A1: 24-hydroxycholesterol 7-alpha-hydroxylase, cytochrome P450, family 39, subfamily A, polypeptide 1

• HSD3B7: hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7

• CYP46A1: cholesterol 24-hydroxylase, cytochrome P450, family 46, subfamily A, polypeptide 1

• CH25H: cholesterol 25-hydroxylase

• CYP7B1: 25-hydroxycholesterol 7-alpha-hydroxylase, cytochrome P450, family 7, subfamily B, polypeptide 1

• CYP27A1: sterol 26-hydroxylase, mitochondrial precursor, cytochrome P450, family 27, subfamily A, polypeptide 1

• CYP8B1: 7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase, cytochrome P450, family 8, subfamily B, polypeptide 1

• AKR1D1: 3-oxo-5beta-steroid 4-dehydrogenase, aldo-keto reductase family 1, member D1

• AKR1C4: 3-alpha hydroxysteroid dehydrogenase, aldo-keto reductase family 1, member C4

• CYP7A1: cholesterol 7-alpha-monooxygenase, cytochrome P450 7A1

• Classic/Neutral BA biosynthesis: Pathway → Disorders of bile acid synthesis and biliary transport