Cholesterol biosynthesis (Homo sapiens)
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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).
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Bibliography
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- Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G.; ''Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.''; PubMed Europe PMC Scholia
- Hogenboom S, Tuyp JJ, Espeel M, Koster J, Wanders RJ, Waterham HR.; ''Phosphomevalonate kinase is a cytosolic protein in humans.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- Laden BP, Tang Y, Porter TD.; ''Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase.''; PubMed Europe PMC Scholia
- Van Tamelen EE, Willett JD, Clayton RB, Lord KE.; ''Enzymic conversion of squalene 2,3-oxide to lanosterol and cholesterol.''; PubMed Europe PMC Scholia
- 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
- 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
- KANDUTSCH AA, RUSSELL AE.; ''Preputial gland tumor sterols. 3. A metabolic pathway from lanosterol to cholesterol.''; PubMed Europe PMC Scholia
- Sung CK, Shibuya M, Sankawa U, Ebizuka Y.; ''Molecular cloning of cDNA encoding human lanosterol synthase.''; PubMed Europe PMC Scholia
- 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
- Hahn FM, Xuan JW, Chambers AF, Poulter CD.; ''Human isopentenyl diphosphate: dimethylallyl diphosphate isomerase: overproduction, purification, and characterization.''; PubMed Europe PMC Scholia
- 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
- Toth MJ, Huwyler L.; ''Molecular cloning and expression of the cDNAs encoding human and yeast mevalonate pyrophosphate decarboxylase.''; PubMed Europe PMC Scholia
- 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
- Rudney H, Sexton RC.; ''Regulation of cholesterol biosynthesis.''; PubMed Europe PMC Scholia
- 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
- Russell DW.; ''Cholesterol biosynthesis and metabolism.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Hogenboom S, Tuyp JJ, Espeel M, Koster J, Wanders RJ, Waterham HR.; ''Mevalonate kinase is a cytosolic enzyme in humans.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- Herdendorf TJ, Miziorko HM.; ''Phosphomevalonate kinase: functional investigation of the recombinant human enzyme.''; PubMed Europe PMC Scholia
- Li L, Kaplan J.; ''Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue.''; PubMed Europe PMC Scholia
- 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
- Herman GE.; ''Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes.''; PubMed Europe PMC Scholia
- Kuzuguchi T, Morita Y, Sagami I, Sagami H, Ogura K.; ''Human geranylgeranyl diphosphate synthase. cDNA cloning and expression.''; PubMed Europe PMC Scholia
- 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
- Moebius FF, Fitzky BU, Lee JN, Paik YK, Glossmann H.; ''Molecular cloning and expression of the human delta7-sterol reductase.''; PubMed Europe PMC Scholia
- Strushkevich N, Usanov SA, Park HW.; ''Structural basis of human CYP51 inhibition by antifungal azoles.''; PubMed Europe PMC Scholia
- 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
- Gaylor JL.; ''Membrane-bound enzymes of cholesterol synthesis from lanosterol.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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Name | Type | Database reference | Comment |
---|---|---|---|
4,4-
dimethylcholesta-8 (9),14,24-trien- 3beta-ol | Metabolite | REACT_10169 (Reactome) ![]() | |
4,4-
dimethylcholesta-8 (9),14,24-trien- 3beta-ol | Metabolite | REACT_10253 (Reactome) ![]() | |
4,4-dimethylcholesta-8
(9),24-dien-3beta-ol | Metabolite | REACT_10787 (Reactome) ![]() | |
4,4-dimethylcholesta-8
(9),24-dien-3beta-ol | Metabolite | REACT_10958 (Reactome) ![]() | |
4-
carboxycholesta-8 (9),24-dien- 3beta-ol | Metabolite | REACT_10167 (Reactome) ![]() | |
4-methyl,4-
carboxycholesta-8(9), 24-dien-3beta-ol | Metabolite | REACT_10298 (Reactome) ![]() | |
4-methylcholesta-8
(9),24-dien-3-one | Metabolite | REACT_10464 (Reactome) ![]() | |
4-methylcholesta-8
(9),24-dien-3beta-ol | Metabolite | REACT_10930 (Reactome) ![]() | |
ADP | Metabolite | 16761 (ChEBI) ![]() | |
ATP | Metabolite | 15422 (ChEBI) ![]() | |
Acetyl-CoA | Metabolite | 15351 (ChEBI) ![]() | |
CO2 | Metabolite | 16526 (ChEBI) ![]() | |
CYP51A1 | Protein | Q16850 (UniProt) ![]() | |
Cholesterol | Metabolite | 16113 (ChEBI) ![]() | |
CoA-SH | Metabolite | 15346 (ChEBI) ![]() | |
DHCR24 | Protein | Q15392 (UniProt) ![]() | |
DHCR7 | Protein | Q9UBM7 (UniProt) ![]() | |
Dimethylallyl
pyrophosphate | Metabolite | 16057 (ChEBI) ![]() | |
EBP | Protein | Q15125 (UniProt) ![]() | |
FDFT (Mg2+
cofactor) | Complex | REACT_9885 (Reactome) ![]() | |
Farnesyl
pyrophosphate | Metabolite | 17407 (ChEBI) ![]() | |
Formate | Metabolite | 30751 (ChEBI) ![]() | |
Geranyl
pyrophosphate | Metabolite | 17211 (ChEBI) ![]() | |
H+ | Metabolite | 15378 (ChEBI) ![]() | |
H2O | Metabolite | 15377 (ChEBI) ![]() | |
HMGCR
dimer | Complex | REACT_9875 (Reactome) ![]() | |
HMGCS1 | Protein | Q01581 (UniProt) ![]() | |
HSD17B7 | Protein | REACT_10277 (Reactome) ![]() | |
IDI1 or 2 | Complex | REACT_9627 (Reactome) ![]() | |
LBR | Protein | Q14739 (UniProt) ![]() | |
LSS | Protein | P48449 (UniProt) ![]() | |
MVD dimer | Complex | REACT_9808 (Reactome) ![]() | |
MVK dimer | Complex | REACT_9683 (Reactome) ![]() | |
Mevalonate | Metabolite | 17710 (ChEBI) ![]() | |
Mevalonate-5-
phosphate | Metabolite | 17436 (ChEBI) ![]() | |
Mevalonate-5-
pyrophosphate | Metabolite | 15899 (ChEBI) ![]() | |
NAD+ | Metabolite | 15846 (ChEBI) ![]() | |
NADH | Metabolite | 16908 (ChEBI) ![]() | |
NADP+ | Metabolite | 18009 (ChEBI) ![]() | |
NADPH | Metabolite | 16474 (ChEBI) ![]() | |
NSDHL | Protein | Q15738 (UniProt) ![]() | |
Orthophosphate | Metabolite | 18367 (ChEBI) ![]() | |
Oxygen | Metabolite | 15379 (ChEBI) ![]() | |
PMVK | Protein | Q15126 (UniProt) ![]() | |
SC4MOL | Protein | Q15800 (UniProt) ![]() | |
SC5D | Protein | O75845 (UniProt) ![]() | |
SQLE:FAD | Complex | REACT_9686 (Reactome) ![]() | |
Squalene | Metabolite | 15440 (ChEBI) ![]() | |
Squalene 2,3
epoxide | Metabolite | 15441 (ChEBI) ![]() | |
TM7SF2 | Protein | O76062 (UniProt) ![]() | |
acetoacetyl-CoA | Metabolite | 15345 (ChEBI) ![]() | |
beta-hydroxy-beta-
methylglutaryl-CoA | Metabolite | 15467 (ChEBI) ![]() | |
cholesta-5,7,24-
trien-3beta-ol | Metabolite | 27910 (ChEBI) ![]() | |
cholesta-7,24-
dien-3beta-ol | Metabolite | 16290 (ChEBI) ![]() | |
cholesta-8(9),24-
dien-3-one | Metabolite | REACT_10977 (Reactome) ![]() | |
delta3-isopentenyl
pyrophosphate | Metabolite | 16584 (ChEBI) ![]() | |
desmosterol | Metabolite | 17737 (ChEBI) ![]() | |
lanosterol | Metabolite | 16521 (ChEBI) ![]() | |
prenyltransferase | Unknown | REACT_26922 (Reactome) ![]() | |
presqualene
diphosphate | Metabolite | 15442 (ChEBI) ![]() | |
pyrophos
phate | Metabolite | 29888 (ChEBI) ![]() | |
pyrophosp
hate | Metabolite | 29888 (ChEBI) ![]() | |
zymosterol | Metabolite | 18252 (ChEBI) ![]() |
Annotated Interactions
No annotated interactions