Cholesterol biosynthesis (Homo sapiens)

From WikiPathways

Revision as of 21:50, 4 March 2011 by MaintBot (Talk | contribs)
Jump to: navigation, search
1-515-172327, 28252662614202111, 12191315-1718632319, 1029, 3022247, 82524endoplasmic reticulum membranecytosolnuclear envelopeNADPHH+NADP+DHCR24NADPH4,4-dimethylcholesta-8(9),24-dien-3beta-ollanosterolNADHNADPHNADP+4-methylcholesta-8(9),24-dien-3-onebeta-hydroxy-beta-methylglutaryl-CoAADPOrthophosphateATPH+CoA-SHNADP+HMGCR dimerCYP51A14,4-dimethylcholesta-8(9),24-dien-3beta-olATPMVD dimerATPMevalonateH2OCO2OxygenpyrophosphateOxygenH+SqualeneNADP+pyrophosphateH2OH+NADPHcholesta-5,7,24-trien-3beta-olSC4MOLMevalonate-5-phosphateNADPHprenyltransferaseH2ONADP+HMGCS1IDI1 or 2H+TM7SF2NADHH+4,4-dimethylcholesta-8(9),14,24-trien-3beta-olNADPHCholesterolPMVKzymosterolNAD+LSSH+MVK dimerdesmosterolNADPHH2OCO2NADP+4-methylcholesta-8(9),24-dien-3beta-olH+CO2NADP+NADP+DHCR7ADPH+ADPMevalonate-5-pyrophosphateH2OEBPFarnesyl pyrophosphateNADP+OxygenpyrophosphateNADPHH2OH+OxygenSC5DNADPH4,4-dimethylcholesta-8(9),14,24-trien-3beta-olNADPHNAD+H+NSDHLFDFT (Mg2+ cofactor)SQLE:FADGeranyl pyrophosphatecholesta-7,24-dien-3beta-olcholesta-8(9),24-dien-3-oneH+HSD17B7NADP+acetoacetyl-CoAdelta3-isopentenyl pyrophosphateNADP+Squalene 2,3 epoxideNADPH4-carboxycholesta-8(9),24-dien-3beta-olDimethylallyl pyrophosphate4-methyl,4-carboxycholesta-8(9),24-dien-3beta-olOxygenH+H+presqualene diphosphateNADP+NADPHH+NADPHFormateLBRAcetyl-CoANADP+


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).

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
4,4-

dimethylcholesta-8 (9),14,24-trien- 3beta-ol

MetaboliteREACT_10169 (Reactome)
4,4-

dimethylcholesta-8 (9),14,24-trien- 3beta-ol

MetaboliteREACT_10253 (Reactome)
4,4-dimethylcholesta-8

(9),24-dien-3beta-ol

MetaboliteREACT_10787 (Reactome)
4,4-dimethylcholesta-8

(9),24-dien-3beta-ol

MetaboliteREACT_10958 (Reactome)
4-

carboxycholesta-8 (9),24-dien- 3beta-ol

MetaboliteREACT_10167 (Reactome)
4-methyl,4-

carboxycholesta-8(9), 24-dien-3beta-ol

MetaboliteREACT_10298 (Reactome)
4-methylcholesta-8

(9),24-dien-3-one

MetaboliteREACT_10464 (Reactome)
4-methylcholesta-8

(9),24-dien-3beta-ol

MetaboliteREACT_10930 (Reactome)
ADP Metabolite16761 (ChEBI)
ATP Metabolite15422 (ChEBI)
Acetyl-CoA Metabolite15351 (ChEBI)
CO2 Metabolite16526 (ChEBI)
CYP51A1 ProteinQ16850 (UniProt)
Cholesterol Metabolite16113 (ChEBI)
CoA-SH Metabolite15346 (ChEBI)
DHCR24 ProteinQ15392 (UniProt)
DHCR7 ProteinQ9UBM7 (UniProt)
Dimethylallyl

pyrophosphate

Metabolite16057 (ChEBI)
EBP ProteinQ15125 (UniProt)
FDFT (Mg2+

cofactor)

ComplexREACT_9885 (Reactome)
Farnesyl

pyrophosphate

Metabolite17407 (ChEBI)
Formate Metabolite30751 (ChEBI)
Geranyl

pyrophosphate

Metabolite17211 (ChEBI)
H+ Metabolite15378 (ChEBI)
H2O Metabolite15377 (ChEBI)
HMGCR

dimer

ComplexREACT_9875 (Reactome)
HMGCS1 ProteinQ01581 (UniProt)
HSD17B7 ProteinREACT_10277 (Reactome)
IDI1 or 2 ComplexREACT_9627 (Reactome)
LBR ProteinQ14739 (UniProt)
LSS ProteinP48449 (UniProt)
MVD dimer ComplexREACT_9808 (Reactome)
MVK dimer ComplexREACT_9683 (Reactome)
Mevalonate Metabolite17710 (ChEBI)
Mevalonate-5-

phosphate

Metabolite17436 (ChEBI)
Mevalonate-5-

pyrophosphate

Metabolite15899 (ChEBI)
NAD+ Metabolite15846 (ChEBI)
NADH Metabolite16908 (ChEBI)
NADP+ Metabolite18009 (ChEBI)
NADPH Metabolite16474 (ChEBI)
NSDHL ProteinQ15738 (UniProt)
Orthophosphate Metabolite18367 (ChEBI)
Oxygen Metabolite15379 (ChEBI)
PMVK ProteinQ15126 (UniProt)
SC4MOL ProteinQ15800 (UniProt)
SC5D ProteinO75845 (UniProt)
SQLE:FAD ComplexREACT_9686 (Reactome)
Squalene Metabolite15440 (ChEBI)
Squalene 2,3

epoxide

Metabolite15441 (ChEBI)
TM7SF2 ProteinO76062 (UniProt)
acetoacetyl-CoA Metabolite15345 (ChEBI)
beta-hydroxy-beta-

methylglutaryl-CoA

Metabolite15467 (ChEBI)
cholesta-5,7,24-

trien-3beta-ol

Metabolite27910 (ChEBI)
cholesta-7,24-

dien-3beta-ol

Metabolite16290 (ChEBI)
cholesta-8(9),24-

dien-3-one

MetaboliteREACT_10977 (Reactome)
delta3-isopentenyl

pyrophosphate

Metabolite16584 (ChEBI)
desmosterol Metabolite17737 (ChEBI)
lanosterol Metabolite16521 (ChEBI)
prenyltransferase UnknownREACT_26922 (Reactome)
presqualene

diphosphate

Metabolite15442 (ChEBI)
pyrophos

phate

Metabolite29888 (ChEBI)
pyrophosp

hate

Metabolite29888 (ChEBI)
zymosterol Metabolite18252 (ChEBI)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1795"