HMG-CoA reductase

HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase, officially abbreviated HMGCR) is the rate-controlling is_associated_with::enzyme (NADH-dependent, ; NADPH-dependent, ) of the is_associated_with::mevalonate pathway, the is_associated_with::metabolic pathway that produces is_associated_with::cholesterol and other is_associated_with::isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis. This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the is_associated_with::statins. HMG-CoA reductase is anchored in the membrane of the is_associated_with::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.

In humans, the gene for HMG-CoA reductase is located on the long arm of the fifth is_associated_with::chromosome (5q13.3-14). Related enzymes having the same function are also present in other animals, plants and bacteria.

Structure
The main isoform (isoform 1) of is_associated_with::HMG-CoA reductase in humans is 888 amino acids long. It is a polytopic is_associated_with::transmembrane protein (meaning it possesses many alpha helical transmembrane segments). It contains two main domains: Isoform 2 is 835 amino acids long. This variant is shorter because it lacks an exon in the middle region. This does not affect any of the aforementioned domains.
 * an N-terminal is_associated_with::sterol-sensing domain (amino acid interval: 88-218), which binds sterol groups. Cholesterol binding at this region inhibits the activity of the catalytic domain.
 * a C-terminal catalytic domain (amino acid interval: 489-871), namely the 3-hydroxy-3-methyl-glutaryl-CoA reductase domain. This domain is required for the proper enzymatic activity of the protein.

Function
HMGCR catalyses the conversion of is_associated_with::HMG-CoA to is_associated_with::mevalonic acid, an necessary step in the biosynthesis of cholesterol.:

Drugs
Drugs that inhibit HMG-CoA reductase, known collectively as is_associated_with::HMG-CoA reductase inhibitors (or "statins"), are used to lower serum is_associated_with::cholesterol as a means of reducing the risk for cardiovascular disease.

These drugs include is_associated_with::rosuvastatin (CRESTOR), is_associated_with::lovastatin (Mevacor), is_associated_with::atorvastatin (Lipitor), is_associated_with::pravastatin (Pravachol), is_associated_with::fluvastatin (Lescol), is_associated_with::pitavastatin (Livalo), and is_associated_with::simvastatin (Zocor). is_associated_with::Red yeast rice extract, one of the fungal sources from which the statins were discovered, contains several naturally occurring cholesterol-lowering molecules known as monacolins. The most active of these is monacolin K, or is_associated_with::lovastatin (previously sold under the trade name Mevacor, and now available as generic lovastatin).

is_associated_with::Vytorin is drug that combines the use is_associated_with::simvastatin and is_associated_with::ezetimibe, which slows the formation of cholesterol by every cell in the body, along with ezetimibe reducing absorption of cholesterol, typically by about 53%, from the intestines.

Hormones
HMG-CoA reductase is active when blood glucose is high. The basic functions of is_associated_with::insulin and is_associated_with::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 is_associated_with::AMP-activated protein kinase, which responds to an increase in AMP concentration, and also to is_associated_with::leptin (see 4.4, Phosphorylation of reductase).

Clinical significance
Since the reaction catalysed by HMG-CoA reductase is the rate-limiting step in cholesterol synthesis, this enzyme represents the sole major drug target for contemporary cholesterol-lowering drugs in humans. The medical significance of HMG-CoA reductase has continued to expand beyond its direct role in cholesterol synthesis following the discovery that statins can offer cardiovascular health benefits independent of cholesterol reduction. Statins have been shown to have anti-inflammatory properties, most likely as a result of their ability to limit production of key downstream is_associated_with::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 is_associated_with::multiple sclerosis, an inflammatory autoimmune disease.

HMG-CoA reductase is an important developmental enzyme. Inhibition of its activity and the concomitant lack of isoprenoids that yields can lead to germ cell migration defects as well as intracerebral hemorrhage.

Regulation
Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.

Transcription of the reductase gene
Transcription of the reductase is_associated_with::gene is enhanced by the is_associated_with::sterol regulatory element binding protein (SREBP). This protein binds to the is_associated_with::sterol regulatory element (SRE), located on the 5' end of the reductase gene. When SREBP is inactive, it is bound to the ER or is_associated_with::nuclear membrane with another protein called SREBP cleavage-activating protein (SCAP). When is_associated_with::cholesterol levels fall, SREBP is released from the membrane by is_associated_with::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 is_associated_with::mRNA is inhibited by a is_associated_with::mevalonate derivative, which has been reported to be is_associated_with::farnesol, although this role has been disputed.

Degradation of reductase
Rising levels of is_associated_with::sterols increase the susceptibility of the reductase enzyme to ER-associated degradation (is_associated_with::ERAD) and is_associated_with::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 is_associated_with::AMFR, serving as a signal for proteolytic degradation.

Phosphorylation of reductase
Short-term regulation of HMG-CoA reductase is achieved by inhibition by is_associated_with::phosphorylation (of Serine 872, in humans ). 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 is_associated_with::AMP-activated protein kinase, which also phosphorylates and inactivates is_associated_with::acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid biosynthesis. 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 is_associated_with::AMP-activated protein kinase.

Fairly recently, LKB1 has been identified as a likely AMP kinase kinase, which appears to involve calcium/calmodulin signaling. This pathway likely transduces signals from is_associated_with::leptin, is_associated_with::adiponectin, and other signaling molecules.