Cholesterol biosynthesis (Homo sapiens)

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4, 11, 12, 28, 3021831719, 2415, 2618129313, 149, 16, 222310231179, 16, 22252762120, 32105, 8MVD dimer [cytosol]cytosolendoplasmic reticulum membranenuclear envelopeHMGCR dimer[endoplasmicreticulum membrane]Isopentenyl-diphosphatedelta-isomerase[cytosol]FDFT (Mg2+ cofactor)[endoplasmicreticulum membrane]MVK dimer [cytosol]IDI1 or 2 [cytosol]Hydroxymethylglutaryl CoAreductase[endoplasmicreticulum membrane]SQLE:FAD[endoplasmicreticulum membrane]MVD(2-400) [cytosol]NADP+MVA5PPMSMO1H+HMGCR-1 [endoplasmicreticulum membrane]H+PPiH+IDI1 [cytosol]MVK [cytosol]DHCR24NADP+ZSOLPMVKH+4-methylcholesta-8(9),24-dien-3beta-olDESMOSqualene 2,3 epoxideHMGCR-2 [endoplasmicreticulum membrane]H+NADP+O2Mg2+ [cytosol]HMGCS1LSSH2OFAPPSQEIDI1 or 2EBPSQLE [endoplasmicreticulum membrane]DHCR74,4-dimethylcholesta-8(9),24-dien-3beta-olprenyltransferaseNADP+DMAPPFAD [cytosol]NADP+H2ONADP+H+H2OO2CO2CoA-SHcholesta-7,24-dien-3beta-olNADP+4-carboxycholesta-8(9),24-dien-3beta-olMVK dimerbHMG-CoAO2presqualenediphosphateNADP+Mg2+ [cytosol]CYP51A14-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol4,4-dimethylcholesta-8(9),14,24-trien-3beta-olMVANADPHTM7SF2ACA-CoAH2OATPcholesta-5,7,24-trien-3beta-olH2OH+NADHH+NADPHNADPHNSDHLGPPNADP+MVA5PSC5DNADPHNAD+NAD+O2H+HSD17B7ADPcholesta-8(9),24-dien-3-oneHMGCR dimerCholesterolMVD dimerNADPHNADPHH+4,4-dimethylcholesta-8(9),24-dien-3beta-olNADH4,4-dimethylcholesta-8(9),14,24-trien-3beta-olATPFDFT1 [endoplasmicreticulum membrane]NADP+CO2PPiNADPH4-methylcholesta-8(9),24-dien-3-oneATPAc-CoANADP+IPPPNADPHNADPHH+O2SQLE:FADCO2ADPNADP+PiADPIDI2 [cytosol]H+LNSOLH2ONADPHH+HCOOHNADPHNADPHLBRH+FDFT (Mg2+ cofactor)NADPHNADP+H+PPi


Description

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).Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=191273

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Bibliography

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History

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114644view16:11, 25 January 2021ReactomeTeamReactome version 75
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101225view11:12, 1 November 2018ReactomeTeamreactome version 66
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99853view15:58, 31 October 2018ReactomeTeamreactome version 63
99410view14:35, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99098view12:39, 31 October 2018ReactomeTeamreactome version 62
93876view13:42, 16 August 2017ReactomeTeamreactome version 61
93443view11:23, 9 August 2017ReactomeTeamreactome version 61
86534view09:20, 11 July 2016ReactomeTeamreactome version 56
83203view10:22, 18 November 2015ReactomeTeamVersion54
81583view13:07, 21 August 2015ReactomeTeamVersion53
77044view08:34, 17 July 2014ReactomeTeamFixed remaining interactions
76749view12:11, 16 July 2014ReactomeTeamFixed remaining interactions
76074view10:13, 11 June 2014ReactomeTeamRe-fixing comment source
75784view11:31, 10 June 2014ReactomeTeamReactome 48 Update
75134view14:08, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74781view08:52, 30 April 2014ReactomeTeamReactome46
72909view15:13, 14 December 2013EgonwArgh...
72907view15:11, 14 December 2013EgonwFixed the Uniprot-TrEMBL data sources.
72904view15:07, 14 December 2013Egonw
72903view15:06, 14 December 2013EgonwUpdated the UniProt data source with UniProt/TrEMBL.
68898view17:29, 8 July 2013MaintBotUpdated to 2013 gpml schema
44990view14:36, 6 October 2011MartijnVanIerselOntology Term : 'cholesterol biosynthetic pathway' added !
42157view23:24, 4 March 2011MaintBotModified categories
42018view21:50, 4 March 2011MaintBotAutomatic update
39821view05:51, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
4,4-dimethylcholesta-8(9),14,24-trien-3beta-olMetaboliteCHEBI:17813 (ChEBI)
4,4-dimethylcholesta-8(9),24-dien-3beta-olMetaboliteCHEBI:18364 (ChEBI)
4-carboxycholesta-8(9),24-dien-3beta-olMetaboliteCHEBI:63844 (ChEBI)
4-methyl,4-carboxycholesta-8(9),24-dien-3beta-olMetaboliteCHEBI:63842 (ChEBI)
4-methylcholesta-8(9),24-dien-3-oneMetaboliteCHEBI:50593 (ChEBI)
4-methylcholesta-8(9),24-dien-3beta-olMetaboliteCHEBI:63841 (ChEBI)
ACA-CoAMetaboliteCHEBI:15345 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
CYP51A1ProteinQ16850 (Uniprot-TrEMBL)
CholesterolMetaboliteCHEBI:16113 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DESMOMetaboliteCHEBI:17737 (ChEBI)
DHCR24ProteinQ15392 (Uniprot-TrEMBL)
DHCR7ProteinQ9UBM7 (Uniprot-TrEMBL)
DMAPPMetaboliteCHEBI:16057 (ChEBI)
EBPProteinQ15125 (Uniprot-TrEMBL)
FAD [cytosol]MetaboliteCHEBI:16238 (ChEBI)
FAPPMetaboliteCHEBI:17407 (ChEBI)
FDFT (Mg2+ cofactor)ComplexREACT_9885 (Reactome)
FDFT1 [endoplasmic reticulum membrane]ProteinP37268 (Uniprot-TrEMBL)
GPPMetaboliteCHEBI:17211 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCOOHMetaboliteCHEBI:30751 (ChEBI)
HMGCR dimerComplexREACT_9875 (Reactome)
HMGCR-1 [endoplasmic reticulum membrane]ProteinP04035-1 (Uniprot-TrEMBL)
HMGCR-2 [endoplasmic reticulum membrane]ProteinP04035-2 (Uniprot-TrEMBL)
HMGCS1ProteinQ01581 (Uniprot-TrEMBL)
HSD17B7ProteinP56937 (Uniprot-TrEMBL)
IDI1 [cytosol]ProteinQ13907 (Uniprot-TrEMBL)
IDI1 or 2ComplexREACT_9627 (Reactome)
IDI2 [cytosol]ProteinQ9BXS1 (Uniprot-TrEMBL)
IPPPMetaboliteCHEBI:16584 (ChEBI)
LBRProteinQ14739 (Uniprot-TrEMBL)
LNSOLMetaboliteCHEBI:16521 (ChEBI)
LSSProteinP48449 (Uniprot-TrEMBL)
MSMO1ProteinQ15800 (Uniprot-TrEMBL)
MVA5PMetaboliteCHEBI:17436 (ChEBI)
MVA5PPMetaboliteCHEBI:15899 (ChEBI)
MVAMetaboliteCHEBI:17710 (ChEBI)
MVD dimerComplexREACT_9808 (Reactome)
MVD(2-400) [cytosol]ProteinP53602 (Uniprot-TrEMBL)
MVK [cytosol]ProteinQ03426 (Uniprot-TrEMBL)
MVK dimerComplexREACT_9683 (Reactome)
Mg2+ [cytosol]MetaboliteCHEBI:18420 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NSDHLProteinQ15738 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PMVKProteinQ15126 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PiMetaboliteCHEBI:18367 (ChEBI)
SC5DProteinO75845 (Uniprot-TrEMBL)
SQEMetaboliteCHEBI:15440 (ChEBI)
SQLE [endoplasmic reticulum membrane]ProteinQ14534 (Uniprot-TrEMBL)
SQLE:FADComplexREACT_9686 (Reactome)
Squalene 2,3 epoxideMetaboliteCHEBI:15441 (ChEBI)
TM7SF2ProteinO76062 (Uniprot-TrEMBL)
ZSOLMetaboliteCHEBI:18252 (ChEBI)
bHMG-CoAMetaboliteCHEBI:15467 (ChEBI)
cholesta-5,7,24-trien-3beta-olMetaboliteCHEBI:27910 (ChEBI)
cholesta-7,24-dien-3beta-olMetaboliteCHEBI:16290 (ChEBI)
cholesta-8(9),24-dien-3-oneMetaboliteCHEBI:52386 (ChEBI)
prenyltransferaseREACT_26922 (Reactome)
presqualene diphosphateMetaboliteCHEBI:15442 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
4,4-dimethylcholesta-8(9),14,24-trien-3beta-olArrowREACT_10006 (Reactome)
4,4-dimethylcholesta-8(9),14,24-trien-3beta-olREACT_10070 (Reactome)
4,4-dimethylcholesta-8(9),14,24-trien-3beta-olREACT_10081 (Reactome)
4,4-dimethylcholesta-8(9),14,24-trien-3beta-olREACT_9995 (Reactome)
4,4-dimethylcholesta-8(9),24-dien-3beta-olArrowREACT_10081 (Reactome)
4,4-dimethylcholesta-8(9),24-dien-3beta-olArrowREACT_9995 (Reactome)
4-carboxycholesta-8(9),24-dien-3beta-olArrowREACT_10059 (Reactome)
4-carboxycholesta-8(9),24-dien-3beta-olREACT_9949 (Reactome)
4-methyl,4-carboxycholesta-8(9),24-dien-3beta-olArrowREACT_10070 (Reactome)
4-methyl,4-carboxycholesta-8(9),24-dien-3beta-olREACT_10053 (Reactome)
4-methylcholesta-8(9),24-dien-3-oneArrowREACT_10053 (Reactome)
4-methylcholesta-8(9),24-dien-3-oneREACT_10036 (Reactome)
4-methylcholesta-8(9),24-dien-3beta-olArrowREACT_10036 (Reactome)
4-methylcholesta-8(9),24-dien-3beta-olREACT_10059 (Reactome)
ACA-CoAREACT_9443 (Reactome)
ADPArrowREACT_9448 (Reactome)
ADPArrowREACT_9488 (Reactome)
ADPArrowREACT_9496 (Reactome)
ATPREACT_9448 (Reactome)
ATPREACT_9488 (Reactome)
ATPREACT_9496 (Reactome)
Ac-CoAREACT_9443 (Reactome)
CO2ArrowREACT_10053 (Reactome)
CO2ArrowREACT_9488 (Reactome)
CO2ArrowREACT_9949 (Reactome)
CYP51A1mim-catalysisREACT_10006 (Reactome)
CholesterolArrowREACT_10122 (Reactome)
CoA-SHArrowREACT_9443 (Reactome)
CoA-SHArrowREACT_9482 (Reactome)
DESMOArrowREACT_10029 (Reactome)
DESMOREACT_10122 (Reactome)
DHCR24mim-catalysisREACT_10122 (Reactome)
DHCR7mim-catalysisREACT_10029 (Reactome)
DMAPPArrowREACT_9517 (Reactome)
DMAPPREACT_9467 (Reactome)
EBPmim-catalysisREACT_9999 (Reactome)
FAPPArrowREACT_9451 (Reactome)
FAPPREACT_9512 (Reactome)
FDFT (Mg2+ cofactor)mim-catalysisREACT_9504 (Reactome)
FDFT (Mg2+ cofactor)mim-catalysisREACT_9512 (Reactome)
GPPArrowREACT_9467 (Reactome)
GPPREACT_9451 (Reactome)
H+ArrowREACT_10053 (Reactome)
H+ArrowREACT_9949 (Reactome)
H+REACT_10006 (Reactome)
H+REACT_10029 (Reactome)
H+REACT_10036 (Reactome)
H+REACT_10059 (Reactome)
H+REACT_10070 (Reactome)
H+REACT_10079 (Reactome)
H+REACT_10081 (Reactome)
H+REACT_10092 (Reactome)
H+REACT_10122 (Reactome)
H+REACT_9420 (Reactome)
H+REACT_9482 (Reactome)
H+REACT_9504 (Reactome)
H+REACT_9995 (Reactome)
H2OArrowREACT_10006 (Reactome)
H2OArrowREACT_10059 (Reactome)
H2OArrowREACT_10070 (Reactome)
H2OArrowREACT_10092 (Reactome)
H2OArrowREACT_9420 (Reactome)
H2OREACT_9443 (Reactome)
HCOOHArrowREACT_10006 (Reactome)
HMGCR dimermim-catalysisREACT_9482 (Reactome)
HMGCS1mim-catalysisREACT_9443 (Reactome)
HSD17B7mim-catalysisREACT_10036 (Reactome)
HSD17B7mim-catalysisREACT_10079 (Reactome)
IDI1 or 2mim-catalysisREACT_9517 (Reactome)
IPPPArrowREACT_9488 (Reactome)
IPPPREACT_9451 (Reactome)
IPPPREACT_9467 (Reactome)
IPPPREACT_9517 (Reactome)
LBRmim-catalysisREACT_9995 (Reactome)
LNSOLArrowREACT_9391 (Reactome)
LNSOLREACT_10006 (Reactome)
LSSmim-catalysisREACT_9391 (Reactome)
MSMO1mim-catalysisREACT_10059 (Reactome)
MSMO1mim-catalysisREACT_10070 (Reactome)
MVA5PArrowREACT_9448 (Reactome)
MVA5PPArrowREACT_9496 (Reactome)
MVA5PPREACT_9488 (Reactome)
MVA5PREACT_9496 (Reactome)
MVAArrowREACT_9482 (Reactome)
MVAREACT_9448 (Reactome)
MVD dimermim-catalysisREACT_9488 (Reactome)
MVK dimermim-catalysisREACT_9448 (Reactome)
NAD+REACT_10053 (Reactome)
NAD+REACT_9949 (Reactome)
NADHArrowREACT_10053 (Reactome)
NADHArrowREACT_9949 (Reactome)
NADP+ArrowREACT_10006 (Reactome)
NADP+ArrowREACT_10029 (Reactome)
NADP+ArrowREACT_10036 (Reactome)
NADP+ArrowREACT_10059 (Reactome)
NADP+ArrowREACT_10070 (Reactome)
NADP+ArrowREACT_10079 (Reactome)
NADP+ArrowREACT_10081 (Reactome)
NADP+ArrowREACT_10092 (Reactome)
NADP+ArrowREACT_10122 (Reactome)
NADP+ArrowREACT_9420 (Reactome)
NADP+ArrowREACT_9482 (Reactome)
NADP+ArrowREACT_9504 (Reactome)
NADP+ArrowREACT_9995 (Reactome)
NADPHREACT_10006 (Reactome)
NADPHREACT_10029 (Reactome)
NADPHREACT_10036 (Reactome)
NADPHREACT_10059 (Reactome)
NADPHREACT_10070 (Reactome)
NADPHREACT_10079 (Reactome)
NADPHREACT_10081 (Reactome)
NADPHREACT_10092 (Reactome)
NADPHREACT_10122 (Reactome)
NADPHREACT_9420 (Reactome)
NADPHREACT_9482 (Reactome)
NADPHREACT_9504 (Reactome)
NADPHREACT_9995 (Reactome)
NSDHLmim-catalysisREACT_10053 (Reactome)
NSDHLmim-catalysisREACT_9949 (Reactome)
O2REACT_10006 (Reactome)
O2REACT_10059 (Reactome)
O2REACT_10070 (Reactome)
O2REACT_10092 (Reactome)
O2REACT_9420 (Reactome)
PMVKmim-catalysisREACT_9496 (Reactome)
PPiArrowREACT_9451 (Reactome)
PPiArrowREACT_9467 (Reactome)
PPiArrowREACT_9504 (Reactome)
PPiArrowREACT_9512 (Reactome)
PiArrowREACT_9488 (Reactome)
REACT_10006 (Reactome) Lanosterol, NADPH + H+, and O2 react to form 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol, NADP+, H2O and formate. This oxidative demethylation reaction, in the endoplasmic reticulum, is catalyzed by lanosterol 14alpha-demethylase (CYP51A1). Although the reaction is annotated here as a single concerted event, studies with purified rat enzyme indicate that the methyl group is converted successively to an alcohol and an aldehyde before being released as formate (Trzaskos et al. 1986; Fischer et al. 1991; Gaylor 2002).
REACT_10029 (Reactome) Cholesta-5,7,24-trien-3beta-ol and NADPH + H+ react to form desmosterol and NADP+. This reaction is catalyzed by DHCR7, associated with the endoplasmic reticulum membrane. The biochemical details of the reaction are inferred from those of the reaction catalyzed by the well-studied rat enzyme (Bae et al. 1999).
REACT_10036 (Reactome) 4-methylcholesta-8(9),24-dien-3-one and NADPH + H+ react to form 4-methylcholesta-8(9),24-dien-3beta-ol and NADP+. This reaction takes place in the endoplasmic reticulum, catalyzed by HSD17B7. Two isoforms of the enzyme due to alternative splicing have been identified but only the first has been tested for enzymatic activity (Marijanovic et al. 2003). The human enzyme has not been studied extensively; molecular details of the reaction are inferred from those worked out in studies of material from rat liver (Gaylor 2002).
REACT_10053 (Reactome) 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol and NAD+ react to form 4-methylcholesta-8(9),24-dien-3-one, CO2, and NADH + H+. This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL (Caldas and Herman 2003). Defects in this enzyme are associated with CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) (Konig et al. 2000), but cholesterol biosynthesis in cells and tissues from affected individuals has not been characterized. Instead, the mechanism and stoichiometry of the reaction are inferred from biochemical studies of partially purified rat enzyme (Rahimtula and Gaylor 1972).
REACT_10059 (Reactome) 4-methylcholesta-8(9),24-dien-3beta-ol, NADPH + H+, and O2 react to form 4-carboxycholesta-8(9),24-dien-3beta-ol, NADP+, and H2O. This reaction, in the endoplasmic reticulum, is catalyzed by SC4MOL (C-4 methylsterol oxidase). The human enzyme has been identified based on its sequence similarity to yeast methyl sterol oxidase (ERG25) and the ability of the cloned human gene to rescue ERG25-deficient yeast cells (Li and Kaplan 1996). The mechanism and stoichiometry of the reaction have been inferred from studies of partially purified rat enzyme (Gaylor et al. 1975; Fukushima et al. 1981).
REACT_10070 (Reactome) 4,4-dimethylcholesta-8(9),24-dien-3beta-ol, NADPH + H+, and O2 react to form 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol, NADP+, and H2O. This reaction, in the endoplasmic reticulum, is catalyzed by SC4MOL (C-4 methylsterol oxidase). The human enzyme has been identified based on its sequence similarity to yeast methyl sterol oxidase (ERG25) and the ability of the cloned human gene to rescue ERG25-deficient yeast cells (Li and Kaplan 1996). The mechanism and stoichiometry of the reaction have been inferred from studies of partially purified rat enzyme (Gaylor et al. 1975; Fukushima et al. 1981).
REACT_10079 (Reactome) Zymosterone (cholesta-8(9),24-dien-3-one) and NADPH + H+ react to form zymosterol (cholesta-8(9),24-dien-3beta-ol) and NADP+. This reaction takes place in the endoplasmic reticulum, catalyzed by HSD17B7. Two isoforms of the enzyme due to alternative splicing have been identified but only the first has been tested for enzymatic activity (Marijanovic et al. 2003). The human enzyme has not been studied extensively; molecular details of the reaction are inferred from those worked out in studies of material from rat liver (Gaylor 2002).
REACT_10081 (Reactome) 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol and NADPH + H+ react to form 4,4-dimethylcholesta-8(9),24-dien-3beta-ol and NADP+, catalyzed by TM7SF2 in the endoplasmic reticulum. TM7SF2 protein has sterol delta14-reductase activity in vitro, and expression of the gene is induced by sterol starvation in human cells, as expected for a gene involved in sterol biosynthesis (Bennati et al. 2006). However, molecular studies of material from an individual with HEM/Greenberg skeletal dysplasia indicate that LBR, a protein that spans the inner nuclear membrane and has both laminin receptor and sterol delta14-reductase activities, is required for normal sterol 14delta-reductase activity in human cells. It remains to be determined whether both LBR and TM7SF2 catalyze this reaction in vivo, and whether the role of TM7SF2 is essential (Waterham et al. 2003).
REACT_10092 (Reactome) Cholesta-7,24-dien-3beta-ol, NADPH + H+, and O2 react to form cholesta-5,7,24-trien-3beta-ol, NADP+, and 2 H2O, catalyzed by SC5D. This reaction takes place in the endoplasmic reticulum. Its biochemical details are inferred from those of the reaction catalyzed by the purified rat protein (Kawata et al. 1985). The role of human SC5D in catalyzing this reaction in vivo is established from studies of patients in whom the enzyme is defective (Brunetti-Pierri et al. 2002; Krakowiak et al. 2003).
REACT_10122 (Reactome) Desmosterol is reduced by NADPH + H+ to form cholesterol and NADP+, catalyzed by DHCR24 associated with the endoplasmic reticulum membrane.
REACT_9391 (Reactome) Lanosterol synthase (LS) catalyzes the cyclization of squalene 2,3-epoxide to lanosterol, a reaction that forms the sterol nucleus.LS is located on the ER membrane and is active as the monomer (Ruf et al, 2004).
REACT_9420 (Reactome) Squalene monooxygenase (squalene epoxidase, SE) is located on the endoplamic reticulum. It catalyzes the oxidation of squalene to squalene 2,3-epoxide. SE seems to be an important rate-limiting enzyme in cholesterol biosynthesis.
REACT_9443 (Reactome) 3-hydroxy-3-methylglutaryl Coenzyme A synthase (HMG-CoA synthase) catalyzes the condensation of acetyl CoA with acetoacetyl CoA to produce HMG-CoA. There are two forms of this enzyme, cytosolic and mitochondrial. The cytosolic form is ubiquitous in the body and is involved in cholesterol biosynthesis and synthesis of other isoprenoid products. The mitochondrial form, found solely in the liver and kidney, is involved in the ketogenic pathway.
REACT_9448 (Reactome) Mevalonate kinase (MK) catalyzes the phosphorylation of mevalonate to mevalonate-5-phosphate.
REACT_9451 (Reactome) Further condensation of an isopentenyl pyrophosphate with geranyl pyrophosphate to form farnesyl pyrophosphate is catalyzed by the prenyltransferases FPP synthase and GGPP synthase. (Kavanagh et al, 2006)
REACT_9467 (Reactome) The family of enzymes called prenyltransferases is involved in the biosynthesis of isoprenoids. Two members of this family are known to catalyse the sequential condensation of isopentenyl pyrophosphate to DMAPP: farnesyl pyrophosphate synthase (FPPS) and geranylgeranyl pyrophosphate synthetase (GGPPS) (Kavanaugh et al, 2006).
REACT_9482 (Reactome) 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the four-electron reduction of HMG-CoA to mevalonate. Mevalonate concentrations in the cell are tightly controlled through the activity of HMGR, which is one of the most highly regulated enzymes known (Goldstein and Brown 1990).
REACT_9488 (Reactome) Mevalonate pyrophosphate decarboxylase (MPD) decarboxylates mevalonate-5-pyrophosphate into isopentenyl pyrophosphate while hydrolysing ATP to ADP and orthophosphate.
REACT_9496 (Reactome) Phosphomevalonate kinase (PMK) catalyzes the reversible, ATP-dependent phosphorylation of mevalonate-5-phosphate, producing mevalonate-5-pyrophosphate.
REACT_9504 (Reactome) In the second step, FDFT catalyzes the reduction of presqualene diphosphate to squalene (Pandit et al. 2000).
REACT_9512 (Reactome) Farnesyl diphosphate farnesyltransferase (FDFT; squalene synthase) catalyzes the reductive dimerization of two farnesyl diphosphate (FPP) molecules to form squalene. This happens in two distinct steps. The first step of dimerization forms presqualene diphosphate (Pandit et al. 2000).
REACT_9517 (Reactome) Cytosolic isopentenyl diphosphate isomerase (IPP isomerase) catalyzes an essential activation step in the isoprenoid biosynthetic pathway. It rearranges isopentenyl pyrophosphate into its highly electrophilic isomer, dimethylallyl pyrophosphate (DMAPP). IPP isomerase may also be located in human peroxisomes but it's function there is not clear.
REACT_9949 (Reactome) 4-carboxycholesta-8(9),24-dien-3beta-ol and NAD+ react to form zymosterone (cholesta-8(9),24-dien-3-one), CO2, and NADH + H+. This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL (Caldas and Herman 2003). Defects in this enzyme are associated with CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) (Konig et al. 2000), but cholesterol biosynthesis in cells and tissues from affceted individuals has not been characterized. Instead, the mechanism and stoichiometry of the reaction are inferred from biochemical studies of partially purified rat enzyme (Rahimtula and Gaylor 1972).
REACT_9995 (Reactome) 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol and NADPH + H+ react to form 4,4-dimethylcholesta-8(9),24-dien-3beta-ol and NADP+, catalyzed by LBR in the nuclear envelope. LBR protein spans the inner nuclear envelope, has an aminoterminal region with properties of a laminin receptor and a carboxyterminal domain with sequence similarity to sterol delta14-reductases (Holmer et al. 1998). Studies of material from an individual with HEM/Greenberg skeletal dysplasia indicate that LBR catalyzes the sterol delta14-reductase step of cholesterol biosynthesis in vivo. DNA sequencing revealed homozygosity for a mutant LBR allele encoding a truncated protein in the affected individual, and cells from the individual accumulated cholesta-8,14-dien-3beta-ol in culture. Transfection of wild-type LBR into the cultured cells reversed the accumulation of cholesta-8,14-dien-3beta-ol (Waterham et al. 2003). This observation is surprising because a second gene, TM7SF2, encodes an efficient sterol delta14-reductase that is localized to the endoplasmic reticulum whose expression is up-regulated in response to sterol depletion (Bennati et al. 2006). The physiological roles of LBR and TM7SF2 in vivo remain to be determined.
REACT_9999 (Reactome) Isomerization of zymosterol to cholesta-7,24-dien-3beta-ol is catalyzed by EBP in the endoplasmic reticulum. The biochemical details of the reaction have been established through studies of purified rat EBP; the role of the human enzyme has been established through studies of patients deficient in it (Derry et al. 1999; Braverman et al. 1999).
SC5Dmim-catalysisREACT_10092 (Reactome)
SQEArrowREACT_9504 (Reactome)
SQEREACT_9420 (Reactome)
SQLE:FADmim-catalysisREACT_9420 (Reactome)
Squalene 2,3 epoxideArrowREACT_9420 (Reactome)
Squalene 2,3 epoxideREACT_9391 (Reactome)
TM7SF2mim-catalysisREACT_10081 (Reactome)
ZSOLArrowREACT_10079 (Reactome)
ZSOLREACT_9999 (Reactome)
bHMG-CoAArrowREACT_9443 (Reactome)
bHMG-CoAREACT_9482 (Reactome)
cholesta-5,7,24-trien-3beta-olArrowREACT_10092 (Reactome)
cholesta-5,7,24-trien-3beta-olREACT_10029 (Reactome)
cholesta-7,24-dien-3beta-olArrowREACT_9999 (Reactome)
cholesta-7,24-dien-3beta-olREACT_10092 (Reactome)
cholesta-8(9),24-dien-3-oneArrowREACT_9949 (Reactome)
cholesta-8(9),24-dien-3-oneREACT_10079 (Reactome)
prenyltransferasemim-catalysisREACT_9451 (Reactome)
prenyltransferasemim-catalysisREACT_9467 (Reactome)
presqualene diphosphateArrowREACT_9512 (Reactome)
presqualene diphosphateREACT_9504 (Reactome)
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