- HMG-CoA reductase
Name = 3-hydroxy-3-methylglutaryl-Coenzyme A reductase
caption = HMG-CoA reductase
width = 200
HGNCid = 5006
Symbol = HMGCR
EntrezGene = 3156
OMIM = 142910
RefSeq = NM_000859
UniProt = P04035
ECnumber = 126.96.36.199
Chromosome = 5
Arm = q
Band = 13.3
LocusSupplementaryData = -q14
HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) is the rate controlling
enzyme(EC number|188.8.131.52) of the mevalonatepathway, the metabolic pathwaythat produces cholesteroland other isoprenoids. This enzyme is the target of the widely available cholesterol lowering drugs known collectively as the statins. HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum, and was long regarded as having seven transmembrane domains, with the active site located in a long carboxyl terminal domain in the cytosol. More recent evidence shows it to contain eight transmembrane domains [Roitelman, J., Olender, E.H., Bar-Nun, S., Dunn, W.A., Simoni, R.D. (1992) Immunological Evidence for 8 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, 959-973.] .
CAS numberfor this enzyme is [37250-24-1] ; the enzyme commission designation is EC 184.108.40.206 for the NADPH dependent enzyme, whereas 220.127.116.11 links to an NADH dependent enzyme.
In humans, the gene for HMG-CoA reductase is located on the long arm of the fifth
chromosome(5q13.3-14). Related enzymes having the same function are also present in other animals, plants and bacteria.
HMG-CoAto mevalonic acid:
Drugs which inhibit HMG-CoA reductase, known collectively as
HMG-CoA reductase inhibitors (or "statins"), are used to lower serum cholesterolas a means of reducing the risk for cardiovascular disease.
These drugs include
lovastatin(Mevacor), atorvastatin(Lipitor), pravastatin(Pravachol), and simvastatin(Zocor). Vytorinis drug that combines the use simvastatinand ezetimibe, which blocks the formation of cholesterol by the body, along with the absorption of cholesterol in the intestines.
HMG-CoA reductase is active when blood glucose is high. The basic functions of
insulinand glucagonare to maintain glucose homeostasis. Thus, in controlling blood sugar levels they indirectly affect the activity of HMG-CoA reductase, but a decrease in activity of the enzyme is caused by an AMP-activated protein kinasewhich responds to an increase in AMP concentration, and also to leptin(see 4.4, Phosphorylation of reductase).
HMG-CoA reductase is a polytopic, transmembrane protein that catalyzes a key step in the mevalonate pathway [http://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-922] which is involved in the synthesis of sterols, isoprenoids and other lipids. In humans, HMG-CoA reductase is the rate-limiting step in cholesterol synthesis and represents the sole major drug target for contemporary cholesterol-lowering drugs.
The medical significance of HMG-CoA reductase has continued to expand beyond its direct role in cholesterol synthesis following the discovery that it can offer cardiovascular health benefits independent of cholesterol reduction [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15853754&query_hl=3&itool=pubmed_DocSum] . Statins have been shown to have anti-inflammatory properties [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16283973&query_hl=6&itool=pubmed_docsum] , most likely as a result of their ability to limit production of key downstream isoprenoids that are required for portions of the inflammatory response. Notably, blocking of isoprenoid synthesis by statins has shown promise in treating a mouse model of
multiple sclerosis, an inflammatory autoimmune disease [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12858078&query_hl=6&itool=pubmed_docsum] .
HMG-CoA reductase is also an important developmental enzyme. Inhibition of its activity and the concomitant lack of isoprenoids that yields can lead to morphological defects [http://mirror.zfin.org/cgi-bin/webdriver?MIval=aa-pubview2.apg&OID=ZDB-PUB-040211-1] .
Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.
Transcription of the reductase gene
Transcription of the reductase
geneis enhanced by the " sterol regulatory element binding protein" (SREBP). This protein binds to the " sterol regulatory element" (SRE), located on the 5' end of the reductase gene. When SREBP is inactive, it is bound to the ER or nuclear membrane. When cholesterollevels fall, SREBP is released from the membrane by proteolysisand migrates to the nucleus, where it binds to the SRE and transcription is enhanced. If cholesterol levels rise, proteolytic cleavage of SREBP from the membrane ceases and any proteins in the nucleus are quickly degraded.
Translation of mRNA
mRNAis inhibited by a mevalonatederivative which has been reported to be farnesol[Meigs T.E., Roseman D.S. Simoni, R.D. (1996) Regulation of 3-hydroxy-3-methylglularyl-coenzyme A reductase degradation by the nonsterol mevalonate metabolite farnesol "in vivo". J. Biol. Chem. 271, 7916-7922.] , [Meigs T.E., Simoni R.D. (1997) Farnesol as a regulator of HMG-CoA reductase degradation: Characterization and role of farnesyl pyrophosphatase. Arch. Biochem. Biophys. 345, 1-9.] , although this role has been disputed [Keller R.K., Zhao, Z.H. Chambers C., Ness G.C. (1996) Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver. Arch. Biochem. Biophys. 328, 324-330.] .
Degradation of reductase
Rising levels of
sterols increases the susceptibility of the reductase enzyme to proteolysis. Helices 2-6 (total of 8) of the HMG-CoA reductase transmembrane domain sense the higher levels of cholesterol and this leads to Lysine 248 being exposed. This lysine residue can become ubiquinated, and this serves as a signal for proteolytic degradation. The protease(SCAP, SCREBP Cleavage Activating Protein) that activates SREBP is also sensitive to levels of sterols.
Phosphorylation of reductase
Short term regulation of HMG-CoA reductase is achieved by inhibition by
phosphorylation(of Serine 872, in humans [Istvan, E.S., et al., "Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis." EMBO J, 2000;19: p. 819-830. PMID 10698924] ). Decades ago it was believed that a cascade of enzymes control the activity of HMG-CoA reductase: an HMG-CoA reductase kinase was thought to inactivate the enzyme, and the kinase in turn was held to be activated via phosphorylation by HMG-CoA reductase kinase kinase. An excellent review on regulation of the mevalonate pathway by Nobel Laureates Joseph Goldstein and Michael Brown adds specifics: HMG-CoA reductase is phosphorylated and inactivated by an AMP-activated protein kinase, which also phosphorylates and inactivates acetyl-CoA carboxylase, the rate limiting enzyme of fatty acid biosyntheis [Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430.] . Thus, both pathways utilizing acetyl-CoA for lipid synthesis are inactivated when energy charge is low in the cell, and concentrations of AMP rise. There has been a great deal of research on the identity of upstream kinases which phosphorylate and activate the AMP-activated protein kinase[Hardie D. G., Scott J. W., Pan D. A., and Hudson E. R. (2003). Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546, 113-120] . Fairly recently LKB1 has been identified as a likely AMP kinase kinase [Witters L. A., Kemp B. E., and Means A. R. (2005). Chutes and Ladders: the search for protein kinases that act on AMPK. Trends Biochem Sci.] which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin, adiponectin, and other signaling molecules [Hardie D. G., Scott J. W., Pan D. A., and Hudson E. R. (2003). Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546, 113-120] .
[http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/cholesterol.htm Cholesterol Synthesis] - has some good regulatory details
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