Sierra Acai Company
Sierra Acai Company
Open 7 Days a Week
MonaVie Independent Distributor
Distributor Training
Shop Online
Enroll Now
Buy Wholesale and maintain an Active status for 2 months and we will refund your $39 Distributor Fee
Friends
Buy Wholesale and maintain an Active status for 2 months and we will refund your $39 Distributor Fee
16-September-2008 20:42:47 - HMG-CoA reductase HMG-CoA reductase 3-hydroxy-3-methylglutaryl-Coenzyme A reductase Identifiers Symbol HMGCR Entrez 3156 HUGO 5006 OMIM 142910 RefSeq NM_000859 UniProt P04035 Other data EC number 1.1.1.88 Locus Chr. 5 q13.3-q14 HMG-CoA reductase or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR is the rate controlling enzyme EC 1.1.1.88 of the mevalonate pathway, the metabolic pathway that produces cholesterol and 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 1. The CAS number for this enzyme is 37250-24-1; the enzyme commission designation is EC 1.1.1.34 for the NADPH dependent enzyme, whereas 1.1.1.88 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. Contents 1 Reaction 2 Inhibitors 3 Importance 4 Regulation 4.1 Transcription of the reductase gene 4.2 Translation of mRNA 4.3 Degradation of reductase 4.4 Phosphorylation of reductase 5 See also 6 References 7 External links Reaction HMGR converts HMG-CoA to mevalonic acid: Mevalonate pathway Mevalonate pathway Inhibitors Drugs Drugs which inhibit HMG-CoA reductase, known collectively as HMG-CoA reductase inhibitors or statins, are used to lower serum cholesterol as a means of reducing the risk for cardiovascular disease. These drugs include lovastatin Mevacor, atorvastatin Lipitor, pravastatin Pravachol, and simvastatin Zocor. Vytorin is drug that combines the use simvastatin and ezetimibe, which blocks the formation of cholesterol by the body, along with the absorption of cholesterol in the intestines. Hormones HMG-CoA reductase is active when blood glucose is high. The basic functions of insulin and glucagon are 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 kinase which responds to an increase in AMP concentration, and also to leptin see 4.4, Phosphorylation of reductase. Importance HMG-CoA reductase is a polytopic, transmembrane protein that catalyzes a key step in the mevalonate pathway 1 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 2. Statins have been shown to have anti-inflammatory properties 3, 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 4. 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 5. Regulation HMG-CoA reductase-Substrate complex Blue:Coenzyme A, red:HMG, green:NADP HMG-CoA reductase-Substrate complex Blue:Coenzyme A, red:HMG, green:NADP Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation. Transcription of the reductase gene Transcription of the reductase gene is 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 cholesterol levels fall, SREBP is released from the membrane by proteolysis and 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 Translation of mRNA is inhibited by a mevalonate derivative which has been reported to be farnesol 2,3, although this role has been disputed 4. 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 humans5. 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 6. 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 7. Fairly recently LKB1 has been identified as a likely AMP kinase kinase 8 which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin, adiponectin, and other signaling molecules 9. See also Oxidoreductase References ^ 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. ^ 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. ^ 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. ^ 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 ^ Goldstein J.L., Brown M.S. 1990 Regulation of the mevalonate pathway. Nature 343, 425-430. ^ 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 ^ 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. ^ 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 IUBMB entry for 1.1.1.88 BRENDA references for 1.1.1.88 Recommended. PubMed references for 1.1.1.88 PubMed Central references for 1.1.1.88 Google Scholar references for 1.1.1.88 External links Cholesterol Synthesis - has some good regulatory details IUBMB entry for 1.1.1.88 KEGG entry for 1.1.1.88 BRENDA entry for 1.1.1.88 NiceZyme view of 1.1.1.88 EC2PDB: PDB structures for 1.1.1.88 PRIAM entry for 1.1.1.88 PUMA2 entry for 1.1.1.88 IntEnz: Integrated Enzyme entry for 1.1.1.88 MetaCyc entry for 1.1.1.88 Atomic-resolution structures of enzymes belonging to this class This EC 1.1.1 enzyme-related article is a stub. This oxidoreductase article is a stub. v d e Oxidoreductases: alcohol oxidoreductases EC 1.1 1.1.1 NAD/NADP acceptor Carbohydrate dehydrogenases - Alcohol dehydrogenase - Glycerol-3-phosphate dehydrogenase - L-xylulose reductase - Aldose reductase - Lactate dehydrogenase - 3-Hydroxyacyl CoA dehydrogenase - Malate dehydrogenase - Isocitrate dehydrogenase - Phosphogluconate dehydrogenase - Glucose-6-phosphate dehydrogenase - HMG-CoA reductase - Β-Ketoacyl ACP reductase - Hydroxysteroid dehydrogenase: 11 Beta HSD11B1, HSD11B2 - 3 Beta 3-beta-HSD - 17 Beta - Carnitine dehydrogenase - Beta-hydroxybutyryl-CoA dehydrogenase - IMP dehydrogenase - DXP reductoisomerase - L-threonine dehydrogenase 1.1.2 cytochrome acceptor Mannitol dehydrogenase cytochrome - D-lactate dehydrogenase cytochrome - D-lactate dehydrogenase cytochrome c-553 1.1.3 oxygen acceptor Glucose oxidase - L-gulonolactone oxidase - Xanthine oxidase 1.1.4 disulfide as acceptor Vitamin K epoxide reductase - Vitamin-K-epoxide reductase warfarin-insensitive 1.1.5 quinone/similar acceptor Quinoprotein glucose dehydrogenase 1.1.99 other acceptors Choline dehydrogenase v d e Metabolism: lipid metabolism - ketones/mevalonate pathway/cholesterol synthesis enzymes To HMG-CoA Acetyl-Coenzyme A acetyltransferase - HMG-CoA synthase regulated step Ketogenesis HMG-CoA lyase - 3-hydroxybutyrate dehydrogenase - Thiophorase To Mevalonic acid HMG-CoA reductase To DMAPP Mevalonate kinase - Phosphomevalonate kinase - Pyrophosphomevalonate decarboxylase - Isopentenyl-diphosphate delta isomerase To Cholesterols Dimethylallyltranstransferase - Geranyl pyrophosphate - Farnesyl-diphosphate farnesyltransferase - Squalene monooxygenase - Lanosterol synthase - CYP51A1 To Bile acids Cholesterol 7 alpha-hydroxylase see also intermediates Retrieved from http://en..org/wiki/HMG-CoA_reductase Categories: Genes on chromosome 5 | EC 1.1.1 stubs | Oxidoreductase stubs | EC 1.1.1 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Polski Türkçe This page was last modified on 5 August 2008, at 00:1
39 Reasons to Drink Acai Juice Every Day
What is MonaVie - Watch the 8-minute video
Discovering MonaVie Video
The Power of You Video
Effects of MonaVie Active on Antioxidant Capacity in Humans
Log into your Wholesale MonaVie Account
So many of us do not eat a balanced diet, get enough sleep, have too much stress, or are impacted with toxins and pollutants. Drinking 2 ounces of MonaVie twice a day will help your body detoxify as well as build your immune system. Its the smartest thing you can do for yourself, so start today. Buying MonaVie through our company guarantees you support 7 days a week and, if you would like to share MonaVie with your family and friends we will guide you from start to finish.
1. Click on Enroll Now (30 - 55% off retail price)
2. Pay $39 for your Wholesale ID number.
3. NO minimum order required.
4. MonaVie is delivered to your door in 3 to 5 days.