PathwayStep1572 PathwayStep1573 PathwayStep1570 PathwayStep1571 PathwayStep1566 PathwayStep1565 PathwayStep1564 PathwayStep1563 PathwayStep1569 PathwayStep1568 PathwayStep1567 PathwayStep1560 PathwayStep1561 PathwayStep1562 PathwayStep1555 PathwayStep1554 PathwayStep1557 PathwayStep1556 PathwayStep1559 PathwayStep1558 PathwayStep1581 PathwayStep1580 PathwayStep1579 PathwayStep1578 PathwayStep1575 PathwayStep1574 PathwayStep1577 PathwayStep1576 3,7,24THCA [mitochondrial matrix] => 3,7,24THCA [cytosol] TetraHCA is conjugated with Coenzyme A (SLC27A5 BACS) 25(R) TetraHCA-CoA [ cytosol] => 25(R) TetraHCA-CoA [peroxisome] 3,7,24THCA is conjugated with Coenzyme A (SLC27A2 VLCS) TetraHCA is conjugated with Coenzyme A (SLC27A2 VLCS) 3,7,24THCA is conjugated with Coenzyme A (SLC27A5 BACS) 3,7,24THCA-CoA => (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA 25(R) TetraHCA-CoA => (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA 3,7,24THCA-CoA [ cytosol] => 3,7,24THCA-CoA [peroxisome] Cholesterol is hydroxylated to 24-hydroxycholesterol by CYP46A1 Efflux of 24-hydroxycholesterol Influx of 24-hydroxycholesterol 24-hydroxycholesterol is 7alpha-hydroxylated to yield cholest-5-ene-3beta,7alpha,24-triol Cholest-5-ene-3beta,7alpha,24(S)-triol + NAD+ => 4-cholesten-7alpha,24(S)-diol-3-one + NADH + H+ 4-Cholesten-7alpha,24(S)-diol-3-one is 12alpha-hydroxylated to 4-cholesten-7-alpha,12-alpha,24(S)-triol-3-one 4-cholesten-7alpha,12alpha,24(S)-triol-3-one is reduced to 5beta-cholestan-7alpha,12alpha,24(S)-triol-3-one 4-cholesten-7alpha,24(S)-diol-3-one is reduced to 5beta-cholestan-7alpha,24(S)-diol-3-one 5Beta-cholestan-7alpha,12alpha,24(S)-triol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol TetraHCA [mitochondrial matrix] => TetraHCA [cytosol] 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al is oxidized to 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestanoate (3,7,24THCA) 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al is oxidized to 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestanoate (TetraHCA) 5beta-cholestan-3alpha,7alpha,24(S),27-tetrol is oxidized to 3alpha,7alpha,24(S)-trihydroxy-5beta-cholestan-27-al 5beta-cholestan-3alpha,7alpha,12alpha,24(S),27-pentol is oxidized to 3alpha,7alpha,12alpha,24(S)-tetrahydroxy-5beta-cholestan-27-al 5beta-cholestan-3alpha,7alpha,24(S)-triol is hydroxylated to 5beta-cholestan-3alpha,7alpha,24(S), 27-tetrol 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol is hydroxylated to 5beta-cholestan-3alpha,7alpha,12alpha,24(S), 27-pentol 5beta-cholestan-3alpha,7alpha,24(S)-triol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha,7alpha,12alpha,24(S)-tetrol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-7alpha,24(S)-diol-3-one is reduced to 5beta-cholestan-3alpha,7alpha,24(S)-triol Synthesis of bile acids and bile salts via 24-hydroxycholesterol Authored: D'Eustachio, P, 2007-02-23 20:35:09 Edited: D'Eustachio, P, 2007-02-23 20:35:09 GENE ONTOLOGYGO:0006699 In the body, 24-hydroxycholesterol is synthesized in the brain, exported to the liver, and converted there to bile acids and bile salts. This pathway is only a minor source of bile acids and bile salts, but appears to be critical for the disposal of excess cholesterol from the brain (Bjorkhem et al. 1998; Javitt 2002).<p>In the liver, conversion of 24-hydroxycholesterol to bile acids and bile salts is initiated with hydroxylation and oxidoreductase reactions to form 4-cholesten-7alpha,24(S)-diol-3-one. The pathway then branches: hydroxylation of 4-cholesten-7alpha,24(S)-diol-3-one to 4-cholesten-7alpha,12alpha,24(S)-triol-3-one leads ultimately to the formation of cholate, while its reduction to 5beta-cholestan-7alpha,24(S)-diol-3-one leads to chenodeoxycholate formation. In both branches, reactions in the cytosol, the mitochondrial matrix, and the peroxisomal matrix result in modifications to the ring structure, shortening and oxidation of the side chain, conversion to a Coenzyme A derivative, and conjugation with the amino acids glycine or taurine (Russell 2003). These reactions are outlined in the figure below. The final three reactions are identical to ones of bile salt synthesis initiated by 7alpha-hydroxylation and are shown as arrows with no substrates. Pubmed11969205 Pubmed12543708 Pubmed9717719 Reactome Database ID Release 43193775 Reactome, http://www.reactome.org ReactomeREACT_11053 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26