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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 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).[2] Related enzymes having the same function are also present in other animals, plants and bacteria.
[edit] ReactionHMGCR converts HMG-CoA to mevalonic acid:
[edit] Inhibitors[edit] DrugsDrugs that 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.[3] These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol), and simvastatin (Zocor).[4] Red yeast rice extract contains several naturally occurring cholesterol-lowering statins known as monacolins. The most active of these is monacolin K, or lovastatin (previously sold under the trade name Mevacor, and now available as generic lovastatin).[5] 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.[6] [edit] HormonesHMG-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). [edit] ImportanceHMG-CoA reductase is a polytopic, transmembrane protein that catalyzes a key step in the mevalonate pathway (MetaCyc mevalonate pathway), 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.[7] Statins have been shown to have anti-inflammatory properties,[8] most likely as a result of their ability to limit production of key downstream isoprenoids that are required for portions of the inflammatory response. It can be noted that blocking of isoprenoid synthesis by statins has shown promise in treating a mouse model of multiple sclerosis, an inflammatory autoimmune disease.[9] 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.[10] [edit] Regulation Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation. [edit] Transcription of the reductase geneTranscription 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. [edit] Translation of mRNATranslation of mRNA is inhibited by a mevalonate derivative, which has been reported to be farnesol,[11][12]although this role has been disputed.[13] [edit] Degradation of reductaseRising levels of sterols increase the susceptibility of the reductase enzyme to ER-assosiated degradation (ERAD) and proteolysis. Helices 2-6 (total of 8) of the HMG-CoA reductase transmembrane domain sense the higher levels of cholesterol, which leads to the exposure of Lysine 248. This lysine residue can become ubiquinated by the E3 ligase AMFR, serving as a signal for proteolytic degradation. [edit] Phosphorylation of reductaseShort-term regulation of HMG-CoA reductase is achieved by inhibition by phosphorylation (of Serine 872, in humans[14]). Decades ago it was believed that a cascade of enzymes controls 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 biosynthesis.[15] 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 that phosphorylate and activate the AMP-activated protein kinase.[16] Fairly recently, LKB1 has been identified as a likely AMP kinase kinase,[17] which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from leptin, adiponectin, and other signaling molecules.[16] [edit] See also[edit] References
[edit] External links
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