Cholesterol biosynthesis (Homo sapiens)

From WikiPathways

Jump to: navigation, search
17, 19, 23, 35, 4110, 12, 21, 2734203, 8, 10, 271825343, 8157, 112, 3226, 283316, 392010, 27, 29612, 2131524910, 27, 3822, 4013293314, 36, 374, 3014, 36, 371838nuclear envelopeendoplasmic reticulum lumencytosolPiATPFAPPHSD17B7PPi7dhDESOLNADPH4MZYMOLO2IDI1 HCOOHCHOLACA-CoAHMGCR-1 NADPHGPPVitamin D(calciferol)metabolismPSQPPNADPHNSDHLLSSADPSQLE:FADNADHZYMSTNLNADP+H2O4C4MZYMOLADP4CZYMOLFDFT1 dh4MZYMOLAc-CoALTHSOLNADP+SQOXCO2FDFT:Mg2+NADPHATPNADPHH+SC5DCO2H2O4,4DMCHtOLMVK NADP+H2ONADP+O2FDPS,GGPS1H2OH+ADPH2OMVK dimerNADPHNADP+14DMLANOLGGPS1 CoA-SHEBPIDI2 NADPHZYMOLATPH+H2OO2SQNEH2ODHCR77-dehydroCHOLPi14DMLANOLHMGCR dimerH+LNSOLO2H+FDPS NADPHNADPHMg2+ NADP+SC5DACAT2 PLPP6NADPHNADP+HMGCR-2 H2ONADP+H+TM7SF2H2OCO2HMGCS1NADPHCoA-SHO2NADP+H+DHCR24H+CHOLNADPHCHdOLNADP+presqualenemonophosphateMVD dimerPMVKZYMONENADP+DESMOLMVA5PNADP+NADP+ARV1H+CYP51A1NADP+4,4DMCHtOLLBRMSMO1NADP+H+FAD SQLE Mg2+ NADPHDHCR7H+MVADMAPPNADPHNADPHPPiH+EBPNAD+bHMG-CoAIDI1 or 2ACAT2 tetramerH+NADHDHCR24H+Mg2+ O2PPiIPPPNAD+H+MVD H+NADPHAc-CoAH+MVA5PPNADP+1


Description

Cholesterol is synthesized de novo from acetyl CoA. The overall synthetic process is outlined in the attached illustration. 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 zymosterol into cholesterol can follow either of routes, one in which reduction of the double bond in the isooctyl side chain is the final step (cholesterol synthesis via desmosterol, also known as the Bloch pathway) and one in which this reduction is the first step (cholesterol biosynthesis via lathosterol, also known as the Kandutsch-Russell pathway). The former pathway is prominent in the liver and many other tissues while the latter is prominent in skin, where it may serve as the source of the 7-dehydrocholesterol that is the starting point for the synthesis of D vitamins. 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 (Gaylor 2002; Herman 2003; Kandutsch & Russell 1960; Mitsche et al. 2015; Song et al. 2005). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 191273
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Jassal, Bijay

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G.; ''Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.''; PubMed Europe PMC Scholia
  2. Hogenboom S, Tuyp JJ, Espeel M, Koster J, Wanders RJ, Waterham HR.; ''Phosphomevalonate kinase is a cytosolic protein in humans.''; PubMed Europe PMC Scholia
  3. Krakowiak PA, Wassif CA, Kratz L, Cozma D, Kovárová M, Harris G, Grinberg A, Yang Y, Hunter AG, Tsokos M, Kelley RI, Porter FD.; ''Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency.''; PubMed Europe PMC Scholia
  4. Swain E, Stukey J, McDonough V, Germann M, Liu Y, Sturley SL, Nickels JT.; ''Yeast cells lacking the ARV1 gene harbor defects in sphingolipid metabolism. Complementation by human ARV1.''; PubMed Europe PMC Scholia
  5. Rokosz LL, Boulton DA, Butkiewicz EA, Sanyal G, Cueto MA, Lachance PA, Hermes JD.; ''Human cytoplasmic 3-hydroxy-3-methylglutaryl coenzyme A synthase: expression, purification, and characterization of recombinant wild-type and Cys129 mutant enzymes.''; PubMed Europe PMC Scholia
  6. Laden BP, Tang Y, Porter TD.; ''Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase.''; PubMed Europe PMC Scholia
  7. Van Tamelen EE, Willett JD, Clayton RB, Lord KE.; ''Enzymic conversion of squalene 2,3-oxide to lanosterol and cholesterol.''; PubMed Europe PMC Scholia
  8. Brunetti-Pierri N, Corso G, Rossi M, Ferrari P, Balli F, Rivasi F, Annunziata I, Ballabio A, Russo AD, Andria G, Parenti G.; ''Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3beta-hydroxysteroid-delta5-desaturase.''; PubMed Europe PMC Scholia
  9. Bennati AM, Castelli M, Della Fazia MA, Beccari T, Caruso D, Servillo G, Roberti R.; ''Sterol dependent regulation of human TM7SF2 gene expression: role of the encoded 3beta-hydroxysterol Delta14-reductase in human cholesterol biosynthesis.''; PubMed Europe PMC Scholia
  10. KANDUTSCH AA, RUSSELL AE.; ''Preputial gland tumor sterols. 3. A metabolic pathway from lanosterol to cholesterol.''; PubMed Europe PMC Scholia
  11. Sung CK, Shibuya M, Sankawa U, Ebizuka Y.; ''Molecular cloning of cDNA encoding human lanosterol synthase.''; PubMed Europe PMC Scholia
  12. Braverman N, Lin P, Moebius FF, Obie C, Moser A, Glossmann H, Wilcox WR, Rimoin DL, Smith M, Kratz L, Kelley RI, Valle D.; ''Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome.''; PubMed Europe PMC Scholia
  13. Hahn FM, Xuan JW, Chambers AF, Poulter CD.; ''Human isopentenyl diphosphate: dimethylallyl diphosphate isomerase: overproduction, purification, and characterization.''; PubMed Europe PMC Scholia
  14. Kavanagh KL, Guo K, Dunford JE, Wu X, Knapp S, Ebetino FH, Rogers MJ, Russell RG, Oppermann U.; ''The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs.''; PubMed Europe PMC Scholia
  15. Toth MJ, Huwyler L.; ''Molecular cloning and expression of the cDNAs encoding human and yeast mevalonate pyrophosphate decarboxylase.''; PubMed Europe PMC Scholia
  16. Strömstedt M, Rozman D, Waterman MR.; ''The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols.''; PubMed Europe PMC Scholia
  17. Rudney H, Sexton RC.; ''Regulation of cholesterol biosynthesis.''; PubMed Europe PMC Scholia
  18. Marijanovic Z, Laubner D, Moller G, Gege C, Husen B, Adamski J, Breitling R.; ''Closing the gap: identification of human 3-ketosteroid reductase, the last unknown enzyme of mammalian cholesterol biosynthesis.''; PubMed Europe PMC Scholia
  19. Russell DW.; ''Cholesterol biosynthesis and metabolism.''; PubMed Europe PMC Scholia
  20. Caldas H, Herman GE.; ''NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets.''; PubMed Europe PMC Scholia
  21. Derry JM, Gormally E, Means GD, Zhao W, Meindl A, Kelley RI, Boyd Y, Herman GE.; ''Mutations in a delta 8-delta 7 sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. [email protected].''; PubMed Europe PMC Scholia
  22. Song XQ, Fukao T, Yamaguchi S, Miyazawa S, Hashimoto T, Orii T.; ''Molecular cloning and nucleotide sequence of complementary DNA for human hepatic cytosolic acetoacetyl-coenzyme A thiolase.''; PubMed Europe PMC Scholia
  23. Song BL, Javitt NB, DeBose-Boyd RA.; ''Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol.''; PubMed Europe PMC Scholia
  24. Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J.; ''Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.''; PubMed Europe PMC Scholia
  25. Fukunaga K, Arita M, Takahashi M, Morris AJ, Pfeffer M, Levy BD.; ''Identification and functional characterization of a presqualene diphosphate phosphatase.''; PubMed Europe PMC Scholia
  26. Schafer BL, Bishop RW, Kratunis VJ, Kalinowski SS, Mosley ST, Gibson KM, Tanaka RD.; ''Molecular cloning of human mevalonate kinase and identification of a missense mutation in the genetic disease mevalonic aciduria.''; PubMed Europe PMC Scholia
  27. Mitsche MA, McDonald JG, Hobbs HH, Cohen JC.; ''Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways.''; PubMed Europe PMC Scholia
  28. Hogenboom S, Tuyp JJ, Espeel M, Koster J, Wanders RJ, Waterham HR.; ''Mevalonate kinase is a cytosolic enzyme in humans.''; PubMed Europe PMC Scholia
  29. Waterham HR, Koster J, Romeijn GJ, Hennekam RC, Vreken P, Andersson HC, FitzPatrick DR, Kelley RI, Wanders RJ.; ''Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis.''; PubMed Europe PMC Scholia
  30. Tinkelenberg AH, Liu Y, Alcantara F, Khan S, Guo Z, Bard M, Sturley SL.; ''Mutations in yeast ARV1 alter intracellular sterol distribution and are complemented by human ARV1.''; PubMed Europe PMC Scholia
  31. Waterham HR, Koster J, Mooyer P, Noort Gv Gv, Kelley RI, Wilcox WR, Wanders RJ, Hennekam RC, Oosterwijk JC.; ''Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene.''; PubMed Europe PMC Scholia
  32. Herdendorf TJ, Miziorko HM.; ''Phosphomevalonate kinase: functional investigation of the recombinant human enzyme.''; PubMed Europe PMC Scholia
  33. Li L, Kaplan J.; ''Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue.''; PubMed Europe PMC Scholia
  34. Pandit J, Danley DE, Schulte GK, Mazzalupo S, Pauly TA, Hayward CM, Hamanaka ES, Thompson JF, Harwood HJ.; ''Crystal structure of human squalene synthase. A key enzyme in cholesterol biosynthesis.''; PubMed Europe PMC Scholia
  35. Herman GE.; ''Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes.''; PubMed Europe PMC Scholia
  36. Kuzuguchi T, Morita Y, Sagami I, Sagami H, Ogura K.; ''Human geranylgeranyl diphosphate synthase. cDNA cloning and expression.''; PubMed Europe PMC Scholia
  37. Ericsson J, Greene JM, Carter KC, Shell BK, Duan DR, Florence C, Edwards PA.; ''Human geranylgeranyl diphosphate synthase: isolation of the cDNA, chromosomal mapping and tissue expression.''; PubMed Europe PMC Scholia
  38. Moebius FF, Fitzky BU, Lee JN, Paik YK, Glossmann H.; ''Molecular cloning and expression of the human delta7-sterol reductase.''; PubMed Europe PMC Scholia
  39. Strushkevich N, Usanov SA, Park HW.; ''Structural basis of human CYP51 inhibition by antifungal azoles.''; PubMed Europe PMC Scholia
  40. Fukao T, Song XQ, Mitchell GA, Yamaguchi S, Sukegawa K, Orii T, Kondo N.; ''Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases.''; PubMed Europe PMC Scholia
  41. Gaylor JL.; ''Membrane-bound enzymes of cholesterol synthesis from lanosterol.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114644view16:11, 25 January 2021ReactomeTeamReactome version 75
113092view11:15, 2 November 2020ReactomeTeamReactome version 74
112326view15:24, 9 October 2020ReactomeTeamReactome version 73
101225view11:12, 1 November 2018ReactomeTeamreactome version 66
100763view20:37, 31 October 2018ReactomeTeamreactome version 65
100307view19:14, 31 October 2018ReactomeTeamreactome version 64
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

View all...
NameTypeDatabase referenceComment
14DMLANOLMetaboliteCHEBI:18364 (ChEBI)
4,4DMCHtOLMetaboliteCHEBI:17813 (ChEBI)
4C4MZYMOLMetaboliteCHEBI:63842 (ChEBI)
4CZYMOLMetaboliteCHEBI:63844 (ChEBI)
4MZYMOLMetaboliteCHEBI:63841 (ChEBI)
7-dehydroCHOLMetaboliteCHEBI:17759 (ChEBI)
7dhDESOLMetaboliteCHEBI:27910 (ChEBI)
ACA-CoAMetaboliteCHEBI:15345 (ChEBI)
ACAT2 ProteinQ9BWD1 (Uniprot-TrEMBL)
ACAT2 tetramerComplexR-HSA-8848217 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
ARV1ProteinQ9H2C2 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
CHOLMetaboliteCHEBI:16113 (ChEBI)
CHdOLMetaboliteCHEBI:16290 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
CYP51A1ProteinQ16850 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DESMOLMetaboliteCHEBI:17737 (ChEBI)
DHCR24ProteinQ15392 (Uniprot-TrEMBL)
DHCR7ProteinQ9UBM7 (Uniprot-TrEMBL)
DMAPPMetaboliteCHEBI:16057 (ChEBI)
EBPProteinQ15125 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FAPPMetaboliteCHEBI:17407 (ChEBI)
FDFT1 ProteinP37268 (Uniprot-TrEMBL)
FDFT:Mg2+ComplexR-HSA-191320 (Reactome)
FDPS ProteinP14324 (Uniprot-TrEMBL)
FDPS,GGPS1ComplexR-HSA-981567 (Reactome)
GGPS1 ProteinO95749 (Uniprot-TrEMBL)
GPPMetaboliteCHEBI:17211 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCOOHMetaboliteCHEBI:30751 (ChEBI)
HMGCR dimerComplexR-HSA-191277 (Reactome)
HMGCR-1 ProteinP04035-1 (Uniprot-TrEMBL)
HMGCR-2 ProteinP04035-2 (Uniprot-TrEMBL)
HMGCS1ProteinQ01581 (Uniprot-TrEMBL)
HSD17B7ProteinP56937 (Uniprot-TrEMBL)
IDI1 ProteinQ13907 (Uniprot-TrEMBL)
IDI1 or 2ComplexR-HSA-191397 (Reactome)
IDI2 ProteinQ9BXS1 (Uniprot-TrEMBL)
IPPPMetaboliteCHEBI:16584 (ChEBI)
LBRProteinQ14739 (Uniprot-TrEMBL)
LNSOLMetaboliteCHEBI:16521 (ChEBI)
LSSProteinP48449 (Uniprot-TrEMBL)
LTHSOLMetaboliteCHEBI:17168 (ChEBI)
MSMO1ProteinQ15800 (Uniprot-TrEMBL)
MVA5PMetaboliteCHEBI:17436 (ChEBI)
MVA5PPMetaboliteCHEBI:15899 (ChEBI)
MVAMetaboliteCHEBI:17710 (ChEBI)
MVD ProteinP53602 (Uniprot-TrEMBL)
MVD dimerComplexR-HSA-191341 (Reactome)
MVK ProteinQ03426 (Uniprot-TrEMBL)
MVK dimerComplexR-HSA-191285 (Reactome)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NSDHLProteinQ15738 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PLPP6ProteinQ8IY26 (Uniprot-TrEMBL)
PMVKProteinQ15126 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
PSQPPMetaboliteCHEBI:15442 (ChEBI)
PiMetaboliteCHEBI:43474 (ChEBI)
SC5DProteinO75845 (Uniprot-TrEMBL)
SQLE ProteinQ14534 (Uniprot-TrEMBL)
SQLE:FADComplexR-HSA-191413 (Reactome)
SQNEMetaboliteCHEBI:15440 (ChEBI)
SQOXMetaboliteCHEBI:15441 (ChEBI)
TM7SF2ProteinO76062 (Uniprot-TrEMBL)
Vitamin D

(calciferol)

metabolism
PathwayR-HSA-196791 (Reactome) Vitamin D3 (VD3, cholecalciferol) is a steroid hormone that principally plays roles in regulating intestinal calcium absorption and in bone metabolism. It is obtained from the diet and produced in the skin by photolysis of 7-dehydrocholesterol and released into the bloodstream. Very few foods (eg. oily fish, mushrooms exposed to sunlight and cod liver oil) are natural sources of vitamin D. A small number of countries in the world artificially fortify a few foods with vitamin D. The metabolites of vitamin D are carried in the circulation bound to a plasma protein called vitamin D binding protein (GC) (for review see Delanghe et al. 2015, Chun 2012). Vitamin D undergoes two subsequent hydroxylations to form the active form of the vitamin, 1-alpha, 25-dihydroxyvitamin D (1,25(OH)2D). The first hydroxylation takes place in the liver followed by subsequent transport to the kidney where the second hydroxylation takes place. 1,25(OH)2D acts by binding to nuclear vitamin D receptors (Neme et al. 2017) and it has been estimated that upwards of 2000 genes are directly or indirectly regulated which are involved in calcium homeostasis, immune responses, cellular growth, differentiation and apoptosis (Hossein-nezhad et al. 2013, Hossein-nezhad & Holick 2013). Inactivation of 1,25(OH)2D occurs via C23/C24 oxidation catalysed by cytochrome CYP24A1 enzyme (Christakos et al. 2016).
ZYMOLMetaboliteCHEBI:18252 (ChEBI)
ZYMONEMetaboliteCHEBI:52386 (ChEBI)
ZYMSTNLMetaboliteCHEBI:16608 (ChEBI)
bHMG-CoAMetaboliteCHEBI:15467 (ChEBI)
dh4MZYMOLMetaboliteCHEBI:50593 (ChEBI)
presqualene monophosphateMetaboliteCHEBI:134117 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
14DMLANOLArrowR-HSA-194674 (Reactome)
14DMLANOLArrowR-HSA-194698 (Reactome)
4,4DMCHtOLArrowR-HSA-194678 (Reactome)
4,4DMCHtOLR-HSA-194641 (Reactome)
4,4DMCHtOLR-HSA-194674 (Reactome)
4,4DMCHtOLR-HSA-194698 (Reactome)
4C4MZYMOLArrowR-HSA-194641 (Reactome)
4C4MZYMOLR-HSA-194642 (Reactome)
4CZYMOLArrowR-HSA-194669 (Reactome)
4CZYMOLR-HSA-194718 (Reactome)
4MZYMOLArrowR-HSA-194689 (Reactome)
4MZYMOLR-HSA-194669 (Reactome)
7-dehydroCHOLArrowR-HSA-6807053 (Reactome)
7-dehydroCHOLR-HSA-6807055 (Reactome)
7dhDESOLArrowR-HSA-195664 (Reactome)
7dhDESOLR-HSA-196402 (Reactome)
ACA-CoAArrowR-HSA-8848215 (Reactome)
ACA-CoAR-HSA-191323 (Reactome)
ACAT2 tetramermim-catalysisR-HSA-8848215 (Reactome)
ADPArrowR-HSA-191380 (Reactome)
ADPArrowR-HSA-191414 (Reactome)
ADPArrowR-HSA-191422 (Reactome)
ARV1mim-catalysisR-HSA-5250531 (Reactome)
ATPR-HSA-191380 (Reactome)
ATPR-HSA-191414 (Reactome)
ATPR-HSA-191422 (Reactome)
Ac-CoAR-HSA-191323 (Reactome)
Ac-CoAR-HSA-8848215 (Reactome)
CHOLArrowR-HSA-196417 (Reactome)
CHOLArrowR-HSA-5250531 (Reactome)
CHOLArrowR-HSA-6807055 (Reactome)
CHOLR-HSA-5250531 (Reactome)
CHdOLArrowR-HSA-195690 (Reactome)
CHdOLR-HSA-195664 (Reactome)
CO2ArrowR-HSA-191414 (Reactome)
CO2ArrowR-HSA-194642 (Reactome)
CO2ArrowR-HSA-194718 (Reactome)
CYP51A1mim-catalysisR-HSA-194678 (Reactome)
CoA-SHArrowR-HSA-191323 (Reactome)
CoA-SHArrowR-HSA-191352 (Reactome)
CoA-SHArrowR-HSA-8848215 (Reactome)
DESMOLArrowR-HSA-196402 (Reactome)
DESMOLR-HSA-196417 (Reactome)
DHCR24mim-catalysisR-HSA-196417 (Reactome)
DHCR24mim-catalysisR-HSA-6807064 (Reactome)
DHCR7mim-catalysisR-HSA-196402 (Reactome)
DHCR7mim-catalysisR-HSA-6807055 (Reactome)
DMAPPArrowR-HSA-191382 (Reactome)
DMAPPR-HSA-191322 (Reactome)
EBPmim-catalysisR-HSA-195690 (Reactome)
EBPmim-catalysisR-HSA-6807052 (Reactome)
FAPPArrowR-HSA-191303 (Reactome)
FAPPR-HSA-191405 (Reactome)
FDFT:Mg2+mim-catalysisR-HSA-191402 (Reactome)
FDFT:Mg2+mim-catalysisR-HSA-191405 (Reactome)
FDPS,GGPS1mim-catalysisR-HSA-191303 (Reactome)
FDPS,GGPS1mim-catalysisR-HSA-191322 (Reactome)
GPPArrowR-HSA-191322 (Reactome)
GPPR-HSA-191303 (Reactome)
H+ArrowR-HSA-194642 (Reactome)
H+ArrowR-HSA-194718 (Reactome)
H+R-HSA-191299 (Reactome)
H+R-HSA-191352 (Reactome)
H+R-HSA-191402 (Reactome)
H+R-HSA-194632 (Reactome)
H+R-HSA-194641 (Reactome)
H+R-HSA-194669 (Reactome)
H+R-HSA-194674 (Reactome)
H+R-HSA-194678 (Reactome)
H+R-HSA-194689 (Reactome)
H+R-HSA-194698 (Reactome)
H+R-HSA-195664 (Reactome)
H+R-HSA-196402 (Reactome)
H+R-HSA-196417 (Reactome)
H+R-HSA-6807053 (Reactome)
H+R-HSA-6807055 (Reactome)
H+R-HSA-6807064 (Reactome)
H2OArrowR-HSA-191299 (Reactome)
H2OArrowR-HSA-191323 (Reactome)
H2OArrowR-HSA-194641 (Reactome)
H2OArrowR-HSA-194669 (Reactome)
H2OArrowR-HSA-194678 (Reactome)
H2OArrowR-HSA-195664 (Reactome)
H2OArrowR-HSA-6807053 (Reactome)
H2OArrowR-HSA-8848215 (Reactome)
H2OR-HSA-8952137 (Reactome)
HCOOHArrowR-HSA-194678 (Reactome)
HMGCR dimermim-catalysisR-HSA-191352 (Reactome)
HMGCS1mim-catalysisR-HSA-191323 (Reactome)
HSD17B7mim-catalysisR-HSA-194632 (Reactome)
HSD17B7mim-catalysisR-HSA-194689 (Reactome)
IDI1 or 2mim-catalysisR-HSA-191382 (Reactome)
IPPPArrowR-HSA-191414 (Reactome)
IPPPR-HSA-191303 (Reactome)
IPPPR-HSA-191322 (Reactome)
IPPPR-HSA-191382 (Reactome)
LBRmim-catalysisR-HSA-194674 (Reactome)
LNSOLArrowR-HSA-191366 (Reactome)
LNSOLR-HSA-194678 (Reactome)
LSSmim-catalysisR-HSA-191366 (Reactome)
LTHSOLArrowR-HSA-6807052 (Reactome)
LTHSOLR-HSA-6807053 (Reactome)
MSMO1mim-catalysisR-HSA-194641 (Reactome)
MSMO1mim-catalysisR-HSA-194669 (Reactome)
MVA5PArrowR-HSA-191380 (Reactome)
MVA5PPArrowR-HSA-191422 (Reactome)
MVA5PPR-HSA-191414 (Reactome)
MVA5PR-HSA-191422 (Reactome)
MVAArrowR-HSA-191352 (Reactome)
MVAR-HSA-191380 (Reactome)
MVD dimermim-catalysisR-HSA-191414 (Reactome)
MVK dimermim-catalysisR-HSA-191380 (Reactome)
NAD+R-HSA-194642 (Reactome)
NAD+R-HSA-194718 (Reactome)
NADHArrowR-HSA-194642 (Reactome)
NADHArrowR-HSA-194718 (Reactome)
NADP+ArrowR-HSA-191299 (Reactome)
NADP+ArrowR-HSA-191352 (Reactome)
NADP+ArrowR-HSA-191402 (Reactome)
NADP+ArrowR-HSA-194632 (Reactome)
NADP+ArrowR-HSA-194641 (Reactome)
NADP+ArrowR-HSA-194669 (Reactome)
NADP+ArrowR-HSA-194674 (Reactome)
NADP+ArrowR-HSA-194678 (Reactome)
NADP+ArrowR-HSA-194689 (Reactome)
NADP+ArrowR-HSA-194698 (Reactome)
NADP+ArrowR-HSA-195664 (Reactome)
NADP+ArrowR-HSA-196402 (Reactome)
NADP+ArrowR-HSA-196417 (Reactome)
NADP+ArrowR-HSA-6807053 (Reactome)
NADP+ArrowR-HSA-6807055 (Reactome)
NADP+ArrowR-HSA-6807064 (Reactome)
NADPHR-HSA-191299 (Reactome)
NADPHR-HSA-191352 (Reactome)
NADPHR-HSA-191402 (Reactome)
NADPHR-HSA-194632 (Reactome)
NADPHR-HSA-194641 (Reactome)
NADPHR-HSA-194669 (Reactome)
NADPHR-HSA-194674 (Reactome)
NADPHR-HSA-194678 (Reactome)
NADPHR-HSA-194689 (Reactome)
NADPHR-HSA-194698 (Reactome)
NADPHR-HSA-195664 (Reactome)
NADPHR-HSA-196402 (Reactome)
NADPHR-HSA-196417 (Reactome)
NADPHR-HSA-6807053 (Reactome)
NADPHR-HSA-6807055 (Reactome)
NADPHR-HSA-6807064 (Reactome)
NSDHLmim-catalysisR-HSA-194642 (Reactome)
NSDHLmim-catalysisR-HSA-194718 (Reactome)
O2R-HSA-191299 (Reactome)
O2R-HSA-194641 (Reactome)
O2R-HSA-194669 (Reactome)
O2R-HSA-194678 (Reactome)
O2R-HSA-195664 (Reactome)
O2R-HSA-6807053 (Reactome)
PLPP6mim-catalysisR-HSA-8952137 (Reactome)
PMVKmim-catalysisR-HSA-191422 (Reactome)
PPiArrowR-HSA-191303 (Reactome)
PPiArrowR-HSA-191322 (Reactome)
PPiArrowR-HSA-191402 (Reactome)
PPiArrowR-HSA-191405 (Reactome)
PSQPPArrowR-HSA-191405 (Reactome)
PSQPPR-HSA-191402 (Reactome)
PSQPPR-HSA-8952137 (Reactome)
PiArrowR-HSA-191414 (Reactome)
PiArrowR-HSA-8952137 (Reactome)
R-HSA-191299 (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.
R-HSA-191303 (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)
R-HSA-191322 (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).
R-HSA-191323 (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.
R-HSA-191352 (Reactome) Dimeric 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR dimer) catalyzes the four-electron reduction of beta-hydroxy-beta-methylglutaryl-CoA (bHMG-CoA) to mevalonate (MVA). MVA concentrations in the cell are tightly controlled through the activity of HMGCR dimer, which is one of the most highly regulated enzymes in metabolism (Goldstein & Brown 1990).
R-HSA-191366 (Reactome) Lanosterol synthase (LSS) catalyzes the cyclization of squalene 2,3-epoxide to lanosterol, a reaction that forms the sterol nucleus. LSS is located on the ER membrane and is active in monomeric form (Ruf et al. 2004).
R-HSA-191380 (Reactome) Mevalonate kinase (MK) catalyzes the phosphorylation of mevalonate to mevalonate-5-phosphate.
R-HSA-191382 (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.
R-HSA-191402 (Reactome) In the second step, FDFT catalyzes the reduction of presqualene diphosphate to squalene (Pandit et al. 2000).
R-HSA-191405 (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).
R-HSA-191414 (Reactome) Mevalonate pyrophosphate decarboxylase (MPD) decarboxylates mevalonate-5-pyrophosphate (MVA5PP) into isopentenyl pyrophosphate (IPPP) while hydrolysing ATP to ADP and orthophosphate (Toth & Huwyler 1996).
R-HSA-191422 (Reactome) Phosphomevalonate kinase (PMK) catalyzes the reversible, ATP-dependent phosphorylation of mevalonate-5-phosphate, producing mevalonate-5-pyrophosphate.
R-HSA-194632 (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).
R-HSA-194641 (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).
R-HSA-194642 (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).
R-HSA-194669 (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).
R-HSA-194674 (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.
R-HSA-194678 (Reactome) Lanosterol 14-alpha demethylase (CYP51A1) catalyses oxidative C14-demethylation of lanosterol (LNSOL) to 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol (4,4DMCHOLtrienol). 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 (Stromstedt et al. 1996, Strushkevich et al. 2010).
R-HSA-194689 (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).
R-HSA-194698 (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).
R-HSA-194718 (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).
R-HSA-195664 (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).
R-HSA-195690 (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).
R-HSA-196402 (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).
R-HSA-196417 (Reactome) Desmosterol is reduced by NADPH + H+ to form cholesterol and NADP+, catalyzed by DHCR24 associated with the endoplasmic reticulum membrane.
R-HSA-5250531 (Reactome) Sterols such as cholesterol (CHOL) synthesised in the endoplasmic reticulum (ER) need to be efficiently transported to the plasma membrane, where 90% of the free sterol pool resides. Conversely, sterols taken up from outside the cell need to be transported back to the ER for esterification to sterol esters. The mechanisms that control this bi-directional movement of sterols are still poorly understood but a likely candidate is protein ARV1 (ARV1). Studies with mutant yeast Arv1 indicate altered intracellular sterol distribution and subsequent defects in sphingolipid metabolism. Human ARV1, a predicted sequence ortholog of yeast Arv1, complements the defects seen associated with deletion of yeast Arv1 (Tinkelenberg et al. 2000, Swain et al. 2002).
R-HSA-6807052 (Reactome) EBP (3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase) associated with the endoplasmic reticulum membrane catalyzes the conversion of ZYMSTNL (zymostenol) to LTHSOL (lathosterol) (Braverman et al. 1999; Derry et al. 1999; Kandutsch & Russell 1960; Mitsche et al. 2015).
R-HSA-6807053 (Reactome) SC5D (lathosterol oxidase) associated with the endoplasmic reticulum desaturates LTHSOL (lathosterol) to 7-dehydroCHOL (7-dehydrocholesterol) (Brunetti-Pierri et al. 2002; Kandutsch & Russell 1960; Krakowiek et al. 2003; Mitsche et al. 2015).
R-HSA-6807055 (Reactome) DHCR7 (7-dehydrocholesterol reductase) associated with the endoplasmic reticulum membrane reduces 7-dehydroCHOL (7-dehydrocholesterol) to CHOL (cholesterol) (Kandutsch & Russell1960; Mitsche et al. 2015; Moebius et al. 1998).
R-HSA-6807064 (Reactome) DHCR24 (delta(24)-sterol reductase) associated with the endoplasmic reticulum membranecatalyzes the reduction of ZYMOL (zymosterol) to ZYMSTNL (zymostenol) (Kandutsch & Russell 1960; Mitsche et al. 2015; Waterham et al. 2001).
R-HSA-8848215 (Reactome) Three human enzymes can utilise ketone bodies for energy production. Two mitochondrial enzymes function in ketolysis whereas a cytosolic enzyme is implicated in cytosolic cholesterol biosynthesis. Cytosolic acetyl-CoA acetyltransferase tetramer (ACAT2 tetramer) (Song et al. 1994) catalyses the condensation of two acetyl-CoA (Ac-CoA) molecules to form acetoacetyl-CoA (ACA-CoA). This is the first step in the biosynthesis of cholesterol (Fukao et al. 1997).
R-HSA-8952137 (Reactome) Phospholipid phosphatase 6 (PLPP6) dephosphorylates presqualene diphosphate (PSQPP) to presqualene monophosphate (PSMP). It may be indirectly involved in innate immunity, as PSDP is a bioactive lipid that rapidly remodels to presqualene monophosphate PSMP upon cell activation. PLPP6 displays diphosphate phosphatase activity with a substrate preference PSDP > FDP > phosphatidic acid.
SC5Dmim-catalysisR-HSA-195664 (Reactome)
SC5Dmim-catalysisR-HSA-6807053 (Reactome)
SQLE:FADmim-catalysisR-HSA-191299 (Reactome)
SQNEArrowR-HSA-191402 (Reactome)
SQNER-HSA-191299 (Reactome)
SQOXArrowR-HSA-191299 (Reactome)
SQOXR-HSA-191366 (Reactome)
TM7SF2mim-catalysisR-HSA-194698 (Reactome)
ZYMOLArrowR-HSA-194632 (Reactome)
ZYMOLR-HSA-195690 (Reactome)
ZYMOLR-HSA-6807064 (Reactome)
ZYMONEArrowR-HSA-194718 (Reactome)
ZYMONER-HSA-194632 (Reactome)
ZYMSTNLArrowR-HSA-6807064 (Reactome)
ZYMSTNLR-HSA-6807052 (Reactome)
bHMG-CoAArrowR-HSA-191323 (Reactome)
bHMG-CoAR-HSA-191352 (Reactome)
dh4MZYMOLArrowR-HSA-194642 (Reactome)
dh4MZYMOLR-HSA-194689 (Reactome)
presqualene monophosphateArrowR-HSA-8952137 (Reactome)
Personal tools