PathwayStep1458 PathwayStep1457 PathwayStep1459 PathwayStep1454 PathwayStep1453 PathwayStep1456 PathwayStep1455 PathwayStep1460 PathwayStep1461 PathwayStep1462 PathwayStep1463 PathwayStep1445 PathwayStep1444 PathwayStep1443 PathwayStep1442 PathwayStep1449 PathwayStep1448 PathwayStep1447 PathwayStep1446 PathwayStep1451 PathwayStep1452 PathwayStep1450 PathwayStep1439 PathwayStep1440 PathwayStep1441 Mevalonate is phosphorylated to mevalonate-5-phosphate Reduction of HMG-CoA produces mevalonate Condensation of acetyl CoA with acetoacetyl CoA to form HMG-CoA Reduction of presqualene diphosphate to form squalene Two FPP molecules dimerize to form presqualene diphosphate Another isopentenyl pyrophosphate is added to geranyl pyrophosphate Addition of isopentenyl pyrophosphate to DMAPP Isopentenyl pyrophosphate rearranges to dimethylallyl pyrophosphate Mevalonate-5-pyrophosphate is decarboxylated Mevalonate-5-phosphate is further phosphorylated. Squalene 2,3-epoxide cyclizes, forming lanosterol Squalene is oxidized to its epoxide 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol is reduced to 4,4-dimethylcholesta-8(9),24-dien-3beta-ol [LBR] Lanosterol is oxidatively demethylated to 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol 4-carboxycholesta-8(9),24-dien-3beta-ol + NAD+ => cholesta-8(9),24-dien-3-one (zymosterone) + CO2 + NADH + H+ 4-methylcholesta-8(9),24-dien-3beta-ol is oxidized to 4-carboxycholesta-8(9),24-dien-3beta-ol 4,4-dimethylcholesta-8(9),24-dien-3beta-ol is oxidized to 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol is reduced to 4,4-dimethylcholesta-8(9),24-dien-3beta-ol [TM7SF2] 4-methylcholesta-8(9),24-dien-3-one is reduced to 4-methylcholesta-8(9),24-dien-3beta-ol 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol + NAD+ => 4-methylcholesta-8(9),24-dien-3-one + CO2 + NADH + H+ Zymosterone (cholesta-8(9),24-dien-3-one) is reduced to zymosterol (cholesta-8(9),24-dien-3beta-ol) Reduction of desmosterol to cholesterol Cholesta-5,7,24-trien-3beta-ol is reduced to desmosterol Cholesta-7,24-dien-3beta-ol is desaturated to form cholesta-5,7,24-trien-3beta-ol Zymosterol => cholesta-7,24-dien-3beta-ol Cholesterol biosynthesis Authored: Jassal, B, 2007-01-24 15:15:12 Cholesterol is synthesized de novo from from acetyl CoA. The overall synthetic process is outlined in the figure below. Enzymes whose regulation plays a major role in determining the rate of cholesterol synthesis in the body are highlighted in red, and connections to other metabolic processes are indicated. The transformation of lanosterol into cholesterol requires multiple steps, including the removal of three methyl groups, the reduction of one double bond and the migration of another. These reactions may not occur in a single fixed order in the body, so the linear pathway laid out here following the work of Gaylor and colleagues (Gaylor 2002) is an oversimplification of the process that occurs in vivo. Defects in several of the enzymes involved in this process are associated with human disease and have provided useful insights into the regulatory roles of cholesterol and its synthetic intermediates in human development (Herman 2003; Song et al. 2005). GENE ONTOLOGYGO:0006695 Pubmed11969204 Pubmed12668600 Pubmed1390320 Pubmed16054061 Pubmed3524618 Reactome Database ID Release 43191273 Reactome, http://www.reactome.org ReactomeREACT_9405 Reviewed: D'Eustachio, P, 2007-01-22 01:32:07