HMG-CoA reductase

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HMG-CoA reductase
HMG-CoA reductase
Rod model of the dimer with spherical caps: coenzyme A (blue), β-hydroxy-β-methylglutaryl acid (red) and NADP (green), according to PDB  1DQA

Existing structural data: s. UniProt

Properties of human protein
Mass / length primary structure 888 amino acids
Secondary to quaternary structure Homodimer
Isoforms 2
Identifier
Gene name HMGCR
External IDs
Transporter classification
TCDB 2.A.6.6.5
designation Sterol transporter family
Enzyme classification
EC, category 1.1.1.34 ,  oxidoreductase
Response type Redox reaction
Substrate 3-hydroxy-3-methylglutaryl-CoA + 2 NAD (P) H / H +
Products ( R ) -Mevalonate + CoA-SH + 2 NAD (P) +
Occurrence
Homology family HMG-CoA reductase
Parent taxon Eukaryotes
Orthologue
human House mouse
Entrez 3156 15357
Ensemble ENSG00000113161 ENSMUSG00000021670
UniProt P04035 Q01237
Refseq (mRNA) NM_000859 NM_008255
Refseq (protein) NP_000850 NP_032281
Gene locus Chr 5: 75.34 - 75.36 Mb Chr 13: 96.65 - 96.67 Mb
PubMed search 3156 15357

HMG-CoA reductase (HMGCR, abbreviation for 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase) is an enzyme ( EC  1.1.1.34 ), which in eukaryotes the 3-hydroxy-3-methylglutaryl-coenzyme-A with the cosubstrate NADPH is reduced to mevalonic acid . In humans, the reaction determines the rate of cholesterol biosynthesis . The inhibition of HMG-CoA reductase therefore leads to a lowering of the cholesterol level . Statins , which are derived from the natural substance lovastatin , a compound related to mevalonic acid, have established themselves as HMG-CoA reductase inhibitors .

The corresponding enzyme active in bacteria ( EC  1.1.1.88 ) uses NADH as a cofactor. In plants, mevalonate is the starting material for isoprenoids .

other names

  • hydroxymethylglutaryl coenzyme A reductase (reduced nicotinamide, adenine dinucleotide phosphate),
  • 3-hydroxy-3-methylglutaryl-CoA reductase,
  • beta-hydroxy-beta-methylglutaryl coenzyme A reductase,
  • hydroxymethylglutaryl CoA reductase (NADPH),
  • S-3-hydroxy-3-methylglutaryl-CoA reductase,
  • NADPH-hydroxymethylglutaryl-CoA reductase,
  • HMGCoA reductase-mevalonate: NADP-oxidoreductase (acetylating-CoA),
  • 3-hydroxy-3-methylglutaryl CoA reductase (NADPH), and
  • hydroxymethylglutaryl-CoA reductase (NADPH2).


Catalyzed reaction

HMG-CoA+ 2 NADPH / H + ⇒ Mevalonate+ CoA-SH + 2 NADP +
HMG-CoA is reduced to mevalonate.

regulation

The transcription of HMG-CoA reductase is regulated by transcription factors that are produced with the help of SCAP (SREBP cleavage activating protein) through MBTPS1 - catalyzed proteolytic cleavage of SREBPs ( sterol regulatory element binding protein ). SCAP is inactivated by bound cholesterol, so that the formation of HMG-CoA reductase decreases with increasing cholesterol concentration. In addition, the HMG-CoA reductase is allosterically inhibited by binding cholesterol ; Lanosterol , a precursor to cholesterol, also acts as an allosteric inhibitor. In the event of a cellular lack of energy with increased AMP concentration, the HMG-CoA reductase is reversibly phosphorylated by AMP-activated protein kinase (AMPK) and thus inactivated; the energy-consuming cholesterol synthesis is thus reduced. If there is a lack of cholesterol, the transcription of the HMG-CoA reductase gene increases again.

Other hormones that regulate HMG-CoA reductase are

literature

  • Georg Löffler: Biochemistry and Pathobiochemistry. 7th edition. Springer, 2003, ISBN 3-540-42295-1 .
  • J. Roitelman, EH Olender, S. Bar-Nun, WA Dunn, RD Simoni: 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. In: J. Cell Biol. 117 (5), June 1992, pp. 959-973. doi: 10.1083 / jcb.117.5.959 . PMC 2289486 (free full text). PMID 1374417 .
  • V. Lindgren, KL Luskey, DW Russell, U. Francke: 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. In: Proc. Natl. Acad. Sci. USA 82 (24), December 1985, pp. 8567-8571. doi: 10.1073 / pnas.82.24.8567 . PMC 390958 (free full text). PMID 3866240 .
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  • Is there a "best" statin drug? In: Johns Hopkins Med. Lett. Health After. 50 15 (11), January 2004, pp. 4-5. PMID 14983817 .
  • YL Lin, TH Wang, MH Lee, NW Su: Biologically active components and nutraceuticals in the Monascus-fermented rice: a review. In: Appl. Microbiol. Biotechnol. 77 (5), January 2008, pp. 965-973. doi: 10.1007 / s00253-007-1256-6 . PMID 18038131 .
  • NA Flores: ezetimibe + simvastatin (Merck / Schering-Plow). In: Current Opinion in Investigational Drugs. 5 (9), September 2004, pp. 984-992. PMID 15503655 .
  • Department of Chemistry and Biochemistry: Biophysical Methods - Lecture 3: Membrane Proteins. University of Guelph, October 1998.
  • C. Arnaud, NR Veillard, F. Mach: Cholesterol-independent effects of statins in inflammation, immunomodulation and atherosclerosis. In: Curr. Drug Targets Cardiovasc. Haematol. Disord. 5 (2), April 2005, pp. 127-134. doi: 10.2174 / 1568006043586198 . PMID 15853754 .
  • Sajoscha Sorrentino, Ulf Landmesser: Nonlipid-lowering effects of statins. In: Curr. Treat. Options Cardiovasc. Med. , 7 (6), December 2005, pp. 459-466. doi: 10.1007 / s11936-005-0031-1 . PMID 16283973 .
  • O. Stüve, S. Youssef, L. Steinman, SS Zamvil: Statins as potential therapeutic agents in neuroinflammatory disorders. In: Current Opinion in Neurology . 16 (3), June 2003, pp. 393-401. doi: 10.1097 / 01.wco.0000073942.19076.d1 . PMID 12858078 .
  • JL Thorpe, M. Doitsidou, SY Ho, E. Raz, SA Farber: Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation. In: Dev. Cell. 6 (2), February 2004, pp. 295-302. doi: 10.1016 / S1534-5807 (04) 00032-2 . PMID 14960282 .
  • S. Eisa-Beygi, G. Hatch, S. Noble, M. Ekker, TM Moon: The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signaling pathway. In: Dev. Biol. 373 (2), January 2013, pp. 258-266. doi: 10.1016 / j.ydbio.2012.11.024 . PMID 23206891 .
  • TE Meigs, DS Roseman, RD Simoni: Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation by the nonsterol mevalonate metabolite farnesol in vivo. In: J. Biol. Chem. 271 (14), April 1996, pp. 7916-7922. doi: 10.1074 / jbc.271.14.7916 . PMID 8626470 .
  • TE Meigs, RD Simoni: Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase. In: Arch. Biochem. Biophys. 345 (1), September 1997, pp. 1-9. doi: 10.1006 / fig . 1997.0200 . PMID 9281305 .
  • RK Keller, Z. Zhao, C. Chambers, GC Ness: Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver. In: Arch. Biochem. Biophys. 328 (2), April 1996, pp. 324-330. doi: 10.1006 / fig.1996.0180 . PMID 8645011 .
  • ES Istvan, M. Palnitkar, SK Buchanan, J. Deisenhofer: Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis. In: EMBO J. 19 (5), March 2000, pp. 819-830. doi: 10.1093 / emboj / 19.5.819 . PMC 305622 (free full text). PMID 10698924 .
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  • DG Hardie, JW Scott, DA Pan, ER Hudson: Management of cellular energy by the AMP-activated protein kinase system. In: FEBS Lett. 546 (1), July 2003, pp. 113-120. doi: 10.1016 / S0014-5793 (03) 00560-X . PMID 12829246 .
  • LA Witters, BE Kemp, AR Means: Chutes and Ladders: the search for protein kinases that act on AMPK. In: Trends Biochem. Sci. 31 (1), January 2006, pp. 13-16. doi: 10.1016 / j.tibs.2005.11.009 . PMID 16356723 .

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Cholesterol Biosynthesis  - Learning and Teaching Materials