Alternative (acidic) bile acid biosynthesis pathway (Mus musculus)

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This pathway depicts the alternative (acidic) route of primary bile acid synthesis, in which cholesterol is first hydroxylated on the side chain at C24, C25 or C26 by enzymes such as CYP46A1, CH25H or CYP27A1 to generate regulatory oxysterols including cerebrosterol, 24 , 25 and 27 hydroxycholesterol and their 7α hydroxylated derivatives (for example 7α,24 , 7α,25 and 7α,27 dihydroxycholesterol). These are then further oxidized to 7α,24 , 7α,25 and 7α,26-dihydroxy-4-cholesten-3-one (ST 27:2;(24)O3, ST 27:2;(25)O3, ST 27:2;(26)O3). 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 (ST 27:1;O3) and related intermediates to yield CDCA, and from the other side at 3α,7α,12α-trihydroxy-5β-cholestan-26-al (ST 27:1;O4) and related intermediates to yield CA.

For the metabolite labels, the “ST 27:x;Oy” codes follow the LIPID MAPS sterol sum‑composition notation, in which “ST 27:1;O2” denotes a C27 sterol with one double‑bond equivalent and two oxygens, and the variants used here (for example ST 27:1;(24)O3) extend this format by indicating the position of selected hydroxyl groups, such as a 24‑hydroxy substituent.

To visually simplify the pathway diagram, the following conventions were applied:

(i) overlapping lines: to avoid redundancy, when several conversion reactions occur between metabolites that differ only in the position of their hydroxyl groups, conversion and catalysis edges are visually merged into a single connection for clarity; the underlying reactions remain distinct in the model and are still linked to their specific metabolites and enzymes

and (ii) stacking multiple enzymes: when two or more enzymes catalyse the same conversion, their nodes are placed in a stacked position and their representative catalytic interactions may overlap, but they all possess a unique catalytic interaction to the corresponding conversion, computationally contributing effectively to the catalysed transformation.

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>> Metabolite and enzyme abbreviations used with their full common or systematic 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