The classic bile acid biosynthetic (neutral) pathway

From LipidomicsWiki

The classic bile acid synthesis pathway consists of a cascade of fourteen steps catalyzed by enzymes located in the cytoplasm, microsomes, mitochondria and peroxisomes. Fig. 2 is an abbreviated version of this complex metabolic pathway.In the liver, cholesterol is converted to 7α-hydroxylcholesterol by a microsomal enzyme, cholesterol 7α-hydroxylase, the ratelimiting enzyme of the pathway, which is then converted to 7α-hydroxy-4 cholesten-3-one by a microsomal 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (HSD3B7). Two cytosolic enzymes, Δ4–3-oxosteroid-5β-reductase (AKR1D1) and 3α-hydroxysteroid dehydrogenase (AKR1C4), reduce 7α-hydroxy-4-cholesten-3-one to 5β-cholestan-3α,7α-diol, a precursor of chenodeoxycholic acid (CDCA). For the synthesis of cholic acid (CA), 7α-hydroxy-4- cholesten-3-one is first hydroxylated at the C-12 position by a microsomal sterol 12α- hydroxylase (CYP8B1), and then reduced to 5β-cholestan-3α,7α,12α-triol by AKR1D1 and AKR1C4. Mitochondrial sterol 27-hydroxylase then oxidizes the steroid side-chain of 5β- cholestane-3α,7α-diol and 5β-cholestane-3α,7α,12α-triol (Fig. 52). This enzyme incorporates a hydroxyl group to the C27 position, which is subsequently oxidized to an aldehyde and then to a carboxyl group. The products, 3α,7α,12α-trihydroxy-5β-cholestanoic acid and 3α,7α- dihydroxy-5β-cholestanoic acid, respectively, are ligated to coenzyme A by bile acid CoA ligase activity catalyzed by either a bile acid CoA synthetase (BACS) or very long chain acyl CoA synthetase homology 2. The cholestanoyl-CoAs are subsequently transported into peroxisomes where the side-chain is shortened by one cycle of β-oxidation to release a propionyl-CoA, and the product cholyl-CoA or chenodeoxycholyl-CoA. Four peroxisomal very long chain fatty acid β-oxidation enzymes, 2-methylacyl-CoA racemase, branched-chain acyl CoA oxidase 2, D-type bifunctional enzyme, and thiolase 2 (also known as sterol carrier protein κ) are involved in β-oxidation reactions. To increase the solubility for secretion into the bile, CoA derivatives are conjugated at C24 with either glycine or taurine by bile acid CoA: amino acid N-acyltransferase (BAT). Under physiological pH, bile acids form Na2+ salts, and are referred to as bile salts. In the intestine, some conjugated CA and CDCA are deconjugated and converted to the secondary bile acids, deoxycholic acid (DCA, 3α,12α) and lithocholic acid (LCA, 3α), respectively, by 7α-dehydroxylase in the intestinal bacteria flora, and are excreted into feces. Most CA and CDCA (about 95%) are quantitatively reabsorbed in the intestine and transported back to the liver via portal blood circulation.

fig to be added 1 june 2011 noragon

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