PathwayStep1552 PathwayStep1527 PathwayStep1528 PathwayStep1529 PathwayStep1520 PathwayStep1521 PathwayStep1522 PathwayStep1523 PathwayStep1524 PathwayStep1525 PathwayStep1526 PathwayStep1518 PathwayStep1519 PathwayStep1516 PathwayStep1517 PathwayStep1514 PathwayStep1515 PathwayStep1549 PathwayStep1545 PathwayStep1546 PathwayStep1547 PathwayStep1548 PathwayStep1541 PathwayStep1542 PathwayStep1543 PathwayStep1544 PathwayStep1551 PathwayStep1550 PathwayStep1538 PathwayStep1539 PathwayStep1536 PathwayStep1537 PathwayStep1534 PathwayStep1535 PathwayStep1532 PathwayStep1533 PathwayStep1530 PathwayStep1531 PathwayStep1540 4-cholesten-7alpha-ol-3-one is reduced to 5beta-cholestan-7alpha-ol-3-one 4-cholesten-7alpha, 12alpha-diol-3-one is reduced to 5beta-cholesten-7alpha, 12alpha-diol-3-one 4-Cholesten-7alpha-ol-3-one is 12alpha-hydroxylated to 7-alpha,12-alpha-dihydroxycholest-4-en-3-one 7alpha-hydroxycholesterol is oxidized and isomerized to 4-cholesten-7alpha-ol-3-one Cholesterol is hydroxylated to 7alpha-hydroxycholesterol by CYP7A1 5beta-cholestan-3alpha, 7alpha, 12alpha-triol is translocated from the cytosol to the mitochondrial matrix 5Beta-cholesten-7alpha, 12alpha-diol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha, 12alpha-triol 5beta-cholestan-7alpha-ol-3-one is reduced to 5beta-cholestan-3alpha, 7alpha-diol 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA + H2O => (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA is oxidized to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-one-CoA 3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA + CoASH => chenodeoxycholoyl-CoA (3alpha,7alpha-dihydroxy-5beta-cholan-24-one-CoA) + propionyl CoA Hydrolysis of choloyl-CoA to cholate and CoASH (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA is oxidized to 3alpha,7alpha-dihydroxy-5beta-cholest-24-one-CoA 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA + CoASH => choloyl-CoA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-one-CoA) + propionyl CoA Chenodeoxycholoyl CoA reacts with glycine or taurine to form glycochenodeoxycholate or taurochenodeoxycholate bile salts [peroxisomal matrix] => cholate bile salts [cytosol] cholate [peroxisomal matrix] => cholate [cytosol] Choloyl CoA reacts with glycine or taurine to form glycocholate or taurocholate Transport (efflux) of bile salts by ABCB11 (bile salt export pump) THCA is conjugated with Coenzyme A (SLC27A2 VLCS) DHCA [mitochondrial matrix] => DHCA [cytosol] 3alpha, 7alpha-dihydroxy-5beta-cholestan-26-al is oxidized to 3alpha, 7alpha-dihydroxy-5beta-cholestanoate (DHCA) THCA [mitochondrial matrix] => THCA [cytosol] 5beta-cholestan-3alpha, 7alpha, 26-triol is oxidized to 3alpha, 7alpha-dihydroxy-5beta-cholestan-26-al 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-al is oxidized to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate (THCA) 5beta-cholestan-3alpha, 7alpha-diol is hydroxylated to 5beta-cholestan-3alpha, 7alpha, 26-triol 5beta-cholestan-3alpha,7alpha,12alpha,27-tetrol is oxidized to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-27-al 5beta-cholestan-3alpha, 7alpha-diol is translocated from the cytosol to the mitochondrial matrix 5beta-cholestan-3alpha, 7alpha, 12alpha-triol is hydroxylated to 5beta-cholestan-3alpha, 7alpha, 12alpha, 27-tetrol 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA + H2O => (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA DHCA is conjugated with Coenzyme A (SLC27A2 VLCS) 25(R) THCA-CoA => 25(S) THCA-CoA 25(R) DHCA-CoA => 25(S) DHCA-CoA 25(S) THCA-CoA + O2 => THCA-CoA + H2O2 25(S) DHCA-CoA + O2 => 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA + H2O2 THCA is conjugated with Coenzyme A (SLC27A5 BACS) DHCA is conjugated with Coenzyme A (SLC27A5 BACS) 25(R) THCA-CoA [ cytosol] => 25(R) THCA-CoA [peroxisome] 25(R) DHCA-CoA [ cytosol] => 25(R) DHCA-CoA [peroxisome] Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol Authored: Jassal, B, 2007-01-19 10:34:59 Edited: D'Eustachio, P, 2007-02-12 16:13:17 GENE ONTOLOGYGO:0006699 In the liver, synthesis of bile acids and bile salts is initiated with the conversion of cholesterol to 7alpha-hydroxycholesterol and of 7alpha-hydroxycholesterol to 4-cholesten-7alpha-ol-3-one. The pathway then branches: hydroxylation of 4-cholesten-7alpha-ol-3-one to 4-cholesten-7alpha, 12alpha-diol-3-one leads ultimately to the formation of cholate, while its reduction to 5beta-cholestan-7alpha-ol-3-one leads to chenodeoxycholate formation. The amounts of substrate following each branch appear to be determined by abundance of the hydroxylase enzyme: in human liver, cholate synthesis predominates.<p>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. In the body, glycocholate, taurocholate, glycochenodeoxycholate, and taurochenodeoxycholate are released from hepatocytes into the bile and ultimately into the lumen of the small intestine, where they function as detergents to solubilize dietary fats. The liver synthetic pathway also yields small amounts of bile acids, cholate and deoxycholate, which may play a feedback role in regulating the bile acid synthetic pathway (Russell 2003). These reactions are outlined in the figure below. Pubmed12543708 Reactome Database ID Release 43193368 Reactome, http://www.reactome.org ReactomeREACT_11041 Reviewed: D'Eustachio, P, 2007-04-30 14:43:26