HMG-CoA reduktaza

HMG-CoA reduktaza (3-hidroksi-3-metil-glutaril-CoA reduktaza, HMGCR) je enzim (EC 1.1.1.88) koji ograničava brzinu mevalonatnog puta, metaboličkog puta koji proizvodi holesterol i druge izoprenoide. Normalno je u ćelijama sisara ovaj enzim supresovan holesterolom koji potiče iz internalizacije i degradacije lipoproteina niske gustine (LDL) putem LDL receptora, kao i oksidovanim vrstama holesterola. Kompetitivni inhibitori reduktaze indukuju izražavanje LDL receptora u jeri, čime se povećava katabolizam LDL-a u plazmi, te se snižava koncentracija holesterola u plazmi, što je važna odrednica ateroskleroze.^[1]

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3-hidroksi-3-metilglutaril-CoA reduktaza
PDB prikaz baziran na 1dq8.
Dostupne strukture
1DQ8, 1DQ9, 1DQA, 1HW8, 1HW9, 1HWI, 1HWJ, 1HWK, 1HWL, 2Q1L, 2Q6B, 2Q6C, 2R4F, 3BGL, 3CCT, 3CCW, 3CCZ, 3CD0, 3CD5, 3CD7, 3CDA, 3CDB
Identifikatori
Simboli	HMGCR; LDLCQ3
Vanjski ID	OMIM: 142910 MGI: 96159 HomoloGene: 30994 GeneCards: HMGCR Gene
EC broj	1.1.1.34
Ontologija gena Molekularna funkcija • aktivnost hidroksimetilglutaril-CoA reduktaze (NADPH) • aktivnost hidroksimetilglutaril-CoA reduktaze • aktivnost proteinske homodimerizacije • vezivanje koenzima • NADPH vezivanje Celularna komponenta • peroksizomalna membrana • endoplazmatični retikulum • membrana endoplazmatičnog retikuluma • integralno sa membranom Biološki proces • proces holesterolne biosinteze • starenje • respons na nutrijent • proces izoprenoidne biosinteze
Pregled RNK izražavanja
podaci
Ortolozi
Vrsta	Čovek	Miš
Entrez	3156	15357
Ensembl	ENSG00000113161	ENSMUSG00000021670
UniProt	P04035	E9PVG9
RefSeq (mRNA)	NM_000859.2	NM_008255.2
RefSeq (protein)	NP_000850.1	NP_032281.2
Lokacija (UCSC)	Chr 5: 74.63 - 74.66 Mb	Chr 13: 96.65 - 96.67 Mb
PubMed pretraga

HMG-CoA reduktaza
Identifikatori
EC broj	{{{EC_number}}}
Ontologija gena	AmiGO / EGO
Pretraga

hydroxymethylglutaryl-CoA reduktaza
Identifikatori
EC broj	1.1.1.88
CAS broj	37250-24-1
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB	RCSB PDB PDBe PDBj PDBsum
Ontologija gena	AmiGO / EGO
Pretraga PMC articles PubMed articles NCBI Protein search

Ovaj enzim je biološka meta široko dostupnih lekova za snižavanje nivoa holesterola, kolektivno poznatih kao statini. HMG-CoA reduktaza ze vezana za membranu endoplazmatičnog retikuluma, i dugo se mislilo da ima sedam transmembranskih domena, sa aktivnim mestom lociranim na njenom dugačkom karboksilnom domenu u citozolu. Nedavni nalazi su pokazali da sadrži osam transmembranskih domena.^[2]

Reference

1. „Entrez Gene: HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase”.
2. Roitelman J, Olender EH, Bar-Nun S, Dunn WA, Simoni RD (June 1992). „Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum”. J. Cell Biol. 117 (5): 959–73. DOI:10.1083/jcb.117.5.959. PMC 2289486. PMID 1374417.

Literatura

• Hodge VJ, Gould SJ, Subramani S i dr.. (1992). „Normal cholesterol synthesis in human cells requires functional peroxisomes”. Biochem. Biophys. Res. Commun. 181 (2): 537–41. DOI:10.1016/0006-291X(91)91222-X. PMID 1755834.
• Ramharack R, Tam SP, Deeley RG (1991). „Characterization of three distinct size classes of human 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA: expression of the transcripts in hepatic and nonhepatic cells”. DNA Cell Biol. 9 (9): 677–90. DOI:10.1089/dna.1990.9.677. PMID 1979742.
• Clarke PR, Hardie DG (1990). „Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver”. EMBO J. 9 (8): 2439–46. PMC 552270. PMID 2369897.
• Luskey KL, Stevens B (1985). „Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation”. J. Biol. Chem. 260 (18): 10271–7. PMID 2991281.
• Humphries SE, Tata F, Henry I i dr.. (1986). „The isolation, characterisation, and chromosomal assignment of the gene for human 3-hydroxy-3-methylglutaryl coenzyme A reductase, (HMG-CoA reductase)”. Hum. Genet. 71 (3): 254–8. DOI:10.1007/BF00284585. PMID 2998972.
• Beg ZH, Stonik JA, Brewer HB (1987). „Phosphorylation and modulation of the enzymic activity of native and protease-cleaved purified hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase by a calcium/calmodulin-dependent protein kinase”. J. Biol. Chem. 262 (27): 13228–40. PMID 3308873.
• Osborne TF, Goldstein JL, Brown MS (1985). „5' end of HMG CoA reductase gene contains sequences responsible for cholesterol-mediated inhibition of transcription”. Cell 42 (1): 203–12. DOI:10.1016/S0092-8674(85)80116-1. PMID 3860301.
• Lindgren V, Luskey KL, Russell DW, Francke U (1986). „Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes”. Proc. Natl. Acad. Sci. U.S.A. 82 (24): 8567–71. DOI:10.1073/pnas.82.24.8567. PMC 390958. PMID 3866240.
• Lehoux JG, Kandalaft N, Belisle S, Bellabarba D (1985). „Characterization of 3-hydroxy-3-methylglutaryl coenzyme A reductase in human adrenal cortex”. Endocrinology 117 (4): 1462–8. DOI:10.1210/endo-117-4-1462. PMID 3896758.
• Boguslawski W, Sokolowski W (1984). „HMG-CoA reductase activity in the microsomal fraction from human placenta in early and term pregnancy”. Int. J. Biochem. 16 (9): 1023–6. DOI:10.1016/0020-711X(84)90120-4. PMID 6479432.
• Harwood HJ, Schneider M, Stacpoole PW (1984). „Measurement of human leukocyte microsomal HMG-CoA reductase activity”. J. Lipid Res. 25 (9): 967–78. PMID 6491541.
• Nguyen LB, Salen G, Shefer S i dr.. (1994). „Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis”. Metab. Clin. Exp. 43 (7): 855–9. DOI:10.1016/0026-0495(94)90266-6. PMID 8028508.
• Bennis F, Favre G, Le Gaillard F, Soula G (1993). „Importance of mevalonate-derived products in the control of HMG-CoA reductase activity and growth of human lung adenocarcinoma cell line A549”. Int. J. Cancer 55 (4): 640–5. DOI:10.1002/ijc.2910550421. PMID 8406993.
• Van Doren M, Broihier HT, Moore LA, Lehmann R (1998). „HMG-CoA reductase guides migrating primordial germ cells”. Nature 396 (6710): 466–9. DOI:10.1038/24871. PMID 9853754.
• Cargill M, Altshuler D, Ireland J i dr.. (1999). „Characterization of single-nucleotide polymorphisms in coding regions of human genes”. Nat. Genet. 22 (3): 231–8. DOI:10.1038/10290. PMID 10391209.
• Aboushadi N, Engfelt WH, Paton VG, Krisans SK (1999). „Role of peroxisomes in isoprenoid biosynthesis”. J. Histochem. Cytochem. 47 (9): 1127–32. DOI:10.1177/002215549904700904. PMID 10449533.
• Honda A, Salen G, Honda M i dr.. (2000). „3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity is inhibited by cholesterol and up-regulated by sitosterol in sitosterolemic fibroblasts”. J. Lab. Clin. Med. 135 (2): 174–9. DOI:10.1067/mlc.2000.104459. PMID 10695663.
• Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J (2000). „Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis”. EMBO J. 19 (5): 819–30. DOI:10.1093/emboj/19.5.819. PMC 305622. PMID 10698924.
• Istvan ES, Deisenhofer J (2001). „Structural mechanism for statin inhibition of HMG-CoA reductase”. Science 292 (5519): 1160–4. DOI:10.1126/science.1059344. PMID 11349148.
• Rasmussen LM, Hansen PR, Nabipour MT i dr.. (2002). „Diverse effects of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase on the expression of VCAM-1 and E-selectin in endothelial cells”. Biochem. J. 360 (Pt 2): 363–70. DOI:10.1042/0264-6021:3600363. PMC 1222236. PMID 11716764.

Povezano

• Oksidoreduktaza

Spoljašnje veze

• Cholesterol Synthesis Arhivirano 2017-07-04 na Wayback Machine-u - has some good regulatory details
• Proteopedia HMG-CoA_Reductase - the HMG-CoA Reductase Structure in Interactive 3D