Cholesterol synthesis disorders (WP5193)
Homo sapiens
Cholesterol is synthesized via a cascade of enzymatic reactions known as the mevalonate pathway. This series of reactions is primarily regulated by a rate-limiting step involving the conversion of hydroxyl-methyl glutaryl-coenzyme A (HMG-CoA) into mevalonate. In this pathway multiple diseases and disorders involving the cholesterol synthesis are included and its role depicted in the pathway.
Authors
Eveline Peterse , Denise Slenter , Friederike Ehrhart , and Eric WeitzActivity
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Organisms
Homo sapiensCommunities
Inherited Metabolic Disorders (IMD) Pathways Rare DiseasesAnnotations
Disease Ontology
hypotrichosis 14 Greenberg dysplasia mevalonic aciduria disease porokeratosis X-linked chondrodysplasia punctata 2 cataract 44 Antley-Bixler syndrome CHILD syndrome Smith-Lemli-Opitz syndrome alopecia-mental retardation syndrome 4Pathway Ontology
cholesterol transport pathway altered cholesterol biosynthetic pathway cholesterol metabolic pathway cholesterol biosynthetic pathway desmosterolosis pathwayLabel | Type | Compact URI | Comment |
---|---|---|---|
(r)-mevalonic acid-5-pyrophosphate | Metabolite | wikidata:Q33061105 | |
Dimethylallyl pyrophosphate | Metabolite | chebi:16057 | |
Farnesyl pyrophosphate | Metabolite | hmdb:HMDB00961 | |
squalene | Metabolite | wikidata:Q407560 | |
Desmosterol | Metabolite | chebi:17737 | |
Lathosterol | Metabolite | chebi:17168 | |
(S)-2,3-epoxysqualene | Metabolite | chebi:15441 | |
Mevalonic acid | Metabolite | hmdb:HMDB00227 | |
Zymosterol | Metabolite | chebi:18252 | |
lanosterol | Metabolite | chebi:16521 | |
7-Dehydrocholesterol | Metabolite | hmdb:HMDB00032 | |
(R)-Mevalonic acid 5-phosphate | Metabolite | chebi:17436 | |
isopentenyl pyrophosphate | Metabolite | chebi:128769 | |
cholesterol | Metabolite | chebi:16113 | |
Geranyl-PP | Metabolite | hmdb:HMDB01285 | |
Acetyl-CoA | Metabolite | hmdb:HMDB01206 | |
HMG-CoA | Metabolite | chebi:15467 | |
SQLE | GeneProduct | ensembl:ENSG00000104549 | |
DHCR7 | GeneProduct | ensembl:ENSG00000172893 | |
MSMO1 | GeneProduct | ensembl:ENSG00000052802 | |
LBR | GeneProduct | ensembl:ENSG00000143815 | |
FDFT1 | GeneProduct | ensembl:ENSG00000079459 | |
EBP | GeneProduct | ensembl:ENSG00000147155 | |
HMGCS1 | GeneProduct | ensembl:ENSG00000112972 | |
MVD | GeneProduct | ensembl:ENSG00000167508 | |
PMVK | GeneProduct | ensembl:ENSG00000163344 | |
DHCR24 | GeneProduct | ensembl:ENSG00000116133 | |
FDPS | GeneProduct | ensembl:ENSG00000160752 | |
IDI1 | GeneProduct | ensembl:ENSG00000067064 | |
SC5D | GeneProduct | ensembl:ENSG00000109929 | |
HSD3B2 | GeneProduct | ensembl:ENSG00000203859 | |
CYP51A1 | GeneProduct | ensembl:ENSG00000001630 | |
HMGCR | GeneProduct | ensembl:ENSG00000113161 | |
LSS | GeneProduct | ensembl:ENSG00000160285 | |
MVK | GeneProduct | ensembl:ENSG00000110921 |
References
- Some properties of the microsomal 2,3-oxidosqualene sterol cyclase. Yamamoto S, Lin K, Bloch K. Proc Natl Acad Sci U S A. 1969 May;63(1):110–7. PubMed Europe PMC Scholia
- Molecular cloning and expression of the cDNAs encoding human and yeast mevalonate pyrophosphate decarboxylase. Toth MJ, Huwyler L. J Biol Chem. 1996 Apr 5;271(14):7895–8. PubMed Europe PMC Scholia
- Molecular cloning of human phosphomevalonate kinase and identification of a consensus peroxisomal targeting sequence. Chambliss KL, Slaughter CA, Schreiner R, Hoffmann GF, Gibson KM. J Biol Chem. 1996 Jul 19;271(29):17330–4. PubMed Europe PMC Scholia
- Identification of catalytic residues in human mevalonate kinase. Potter D, Miziorko HM. J Biol Chem. 1997 Oct 10;272(41):25449–54. PubMed Europe PMC Scholia
- Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways. Hinson DD, Chambliss KL, Toth MJ, Tanaka RD, Gibson KM. J Lipid Res. 1997 Nov;38(11):2216–23. PubMed Europe PMC Scholia
- Isopentenyl diphosphate isomerase: a core enzyme in isoprenoid biosynthesis. A review of its biochemistry and function. Ramos-Valdivia AC, van der Heijden R, Verpoorte R. Nat Prod Rep. 1997 Dec;14(6):591–603. PubMed Europe PMC Scholia
- Human geranylgeranyl diphosphate synthase. cDNA cloning and expression. Kuzuguchi T, Morita Y, Sagami I, Sagami H, Ogura K. J Biol Chem. 1999 Feb 26;274(9):5888–94. PubMed Europe PMC Scholia
- Cholesterol biosynthesis from lanosterol. Molecular cloning, tissue distribution, expression, chromosomal localization, and regulation of rat 7-dehydrocholesterol reductase, a Smith-Lemli-Opitz syndrome-related protein. Bae SH, Lee JN, Fitzky BU, Seong J, Paik YK. J Biol Chem. 1999 May 21;274(21):14624–31. PubMed Europe PMC Scholia
- Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase. Laden BP, Tang Y, Porter TD. Arch Biochem Biophys. 2000 Feb 15;374(2):381–8. PubMed Europe PMC Scholia
- Crystal structure of human squalene synthase. A key enzyme in cholesterol biosynthesis. Pandit J, Danley DE, Schulte GK, Mazzalupo S, Pauly TA, Hayward CM, et al. J Biol Chem. 2000 Sep 29;275(39):30610–7. PubMed Europe PMC Scholia
- Structure and regulation of mammalian squalene synthase. Tansey TR, Shechter I. Biochim Biophys Acta. 2000 Dec 15;1529(1–3):49–62. PubMed Europe PMC Scholia
- Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Waterham HR, Koster J, Romeijn GJ, Hennekam RC, Vreken P, Andersson HC, et al. Am J Hum Genet. 2001 Oct;69(4):685–94. PubMed Europe PMC Scholia
- Recombinant squalene synthase. A mechanism for the rearrangement of presqualene diphosphate to squalene. Blagg BSJ, Jarstfer MB, Rogers DH, Poulter CD. J Am Chem Soc. 2002 Jul 31;124(30):8846–53. PubMed Europe PMC Scholia
- Inhibition of cholesterol biosynthesis by Delta22-unsaturated phytosterols via competitive inhibition of sterol Delta24-reductase in mammalian cells. Fernández C, Suárez Y, Ferruelo AJ, Gómez-Coronado D, Lasunción MA. Biochem J. 2002 Aug 15;366(Pt 1):109–19. PubMed Europe PMC Scholia
- THE INTERMEDIARY ROLE OF DELTA-5,7-CHOLESTADIEN-3-BETA-OL IN CHOLESTEROL BIOSYNTHESIS. DEMPSEY ME, SEATON JD, SCHROEPFER GJ Jr, TROCKMAN RW. J Biol Chem. 1964 May;239:1381–7. PubMed Europe PMC Scholia
- Photoaffinity labeling identifies the substrate-binding site of mammalian squalene epoxidase. Lee HK, Zheng YF, Xiao XY, Bai M, Sakakibara J, Ono T, et al. Biochem Biophys Res Commun. 2004 Feb 27;315(1):1–9. PubMed Europe PMC Scholia
- Inhibition of the class II HMG-CoA reductase of Pseudomonas mevalonii. Hedl M, Rodwell VW. Protein Sci. 2004 Jun;13(6):1693–7. PubMed Europe PMC Scholia
- Cytochrome P450 17alpha hydroxylase/17,20 lyase (CYP17) function in cholesterol biosynthesis: identification of squalene monooxygenase (epoxidase) activity associated with CYP17 in Leydig cells. Liu Y, Yao ZX, Papadopoulos V. Mol Endocrinol. 2005 Jul;19(7):1918–31. PubMed Europe PMC Scholia
- Phosphomevalonate kinase: functional investigation of the recombinant human enzyme. Herdendorf TJ, Miziorko HM. Biochemistry. 2006 Mar 14;45(10):3235–42. PubMed Europe PMC Scholia
- The crystal structure of human geranylgeranyl pyrophosphate synthase reveals a novel hexameric arrangement and inhibitory product binding. Kavanagh KL, Dunford JE, Bunkoczi G, Russell RGG, Oppermann U. J Biol Chem. 2006 Aug 4;281(31):22004–12. PubMed Europe PMC Scholia
- Functional evaluation of conserved basic residues in human phosphomevalonate kinase. Herdendorf TJ, Miziorko HM. Biochemistry. 2007 Oct 23;46(42):11780–8. PubMed Europe PMC Scholia
- Cloning and functional analysis of novel short-chain cis-prenyltransferases. Ambo T, Noike M, Kurokawa H, Koyama T. Biochem Biophys Res Commun. 2008 Oct 31;375(4):536–40. PubMed Europe PMC Scholia
- Synthesis of ATP derivatives of compounds of the mevalonate pathway (isopentenyl di- and triphosphate; geranyl di- and triphosphate, farnesyl di- and triphosphate, and dimethylallyl diphosphate) catalyzed by T4 RNA ligase, T4 DNA ligase and other ligases Potential relationship with the effect of bisphosphonates on osteoclasts. Sillero MAG, de Diego A, Tavares JEF, Silva JADC da, Pérez-Zúñiga FJ, Sillero A. Biochem Pharmacol. 2009 Aug 15;78(4):335–43. PubMed Europe PMC Scholia
- The endogenous regulator 24(S),25-epoxycholesterol inhibits cholesterol synthesis at DHCR24 (Seladin-1). Zerenturk EJ, Kristiana I, Gill S, Brown AJ. Biochim Biophys Acta. 2012 Sep;1821(9):1269–77. PubMed Europe PMC Scholia
- SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, et al. Cell Metab. 2013 Dec 3;18(6):920–33. PubMed Europe PMC Scholia