HMG-CoA reductase

3-hydroxy-3-methylglutaryl-CoA reductase
PDB rendering based on 1dq8.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1DQ8, 1DQ9, 1DQA, 1HW8, 1HW9, 1HWI, 1HWJ, 1HWK, 1HWL, 2Q1L, 2Q6B, 2Q6C, 2R4F, 3BGL, 3CCT, 3CCW, 3CCZ, 3CD0, 3CD5, 3CD7, 3CDA, 3CDB
Identifiers
Symbols	HMGCR ; LDLCQ3
External IDs	OMIM: 142910 MGI: 96159 HomoloGene: 30994 ChEMBL: 402 GeneCards: HMGCR Gene
EC number	1.1.1.34
Gene ontology Molecular function • hydroxymethylglutaryl-CoA reductase (NADPH) activity • protein binding • hydroxymethylglutaryl-CoA reductase activity • protein homodimerization activity • coenzyme binding • protein phosphatase 2A binding • NADPH binding Cellular component • intracellular • peroxisomal membrane • endoplasmic reticulum • endoplasmic reticulum membrane • integral component of membrane Biological process • cholesterol biosynthetic process • ubiquinone metabolic process • aging • response to nutrient • isoprenoid biosynthetic process • visual learning • negative regulation of striated muscle cell apoptotic process • positive regulation of cardiac muscle cell apoptotic process • coenzyme A metabolic process • positive regulation of stress-activated MAPK cascade • negative regulation of MAP kinase activity • cellular lipid metabolic process • small molecule metabolic process • myoblast differentiation • response to ethanol • negative regulation of vasodilation • positive regulation of skeletal muscle tissue development • positive regulation of smooth muscle cell proliferation • protein tetramerization • oxidation-reduction process • negative regulation of wound healing • negative regulation of insulin secretion involved in cellular response to glucose stimulus • positive regulation of ERK1 and ERK2 cascade Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3156	15357
Ensembl	ENSG00000113161	ENSMUSG00000021670
UniProt	P04035	Q01237
RefSeq (mRNA)	NM_000859	NM_008255
RefSeq (protein)	NP_000850	NP_032281
Location (UCSC)	Chr 5: 75.34 – 75.36 Mb	Chr 13: 96.65 – 96.67 Mb
PubMed search	[1]	[2]

HMG-CoA reductase
EC number	{{{EC_number}}}
Gene Ontology	AmiGO / EGO

hydroxymethylglutaryl-CoA reductase
Identifiers
EC number	1.1.1.88
CAS number	Template:CAS
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

hydroxymethylglutaryl-CoA reductase
Identifiers
EC number	1.1.1.34
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH-dependent, EC 1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other 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 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.

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.

Structure

The main isoform (isoform 1) of HMG-CoA reductase in humans is 888 amino acids long. It is a polytopic transmembrane protein (meaning it possesses many alpha helical transmembrane segments). It contains two main domains:

• an N-terminal 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.

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.

Function

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

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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|px|alt=Statin Pathway edit]]

File:StatinPathway_WP430.png

Statin Pathway edit

Inhibitors

Drugs

Drugs 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.

These drugs include rosuvastatin (CRESTOR), lovastatin (Mevacor), atorvastatin (Lipitor), pravastatin (Pravachol), fluvastatin (Lescol), pitavastatin (Livalo), and simvastatin (Zocor). 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 lovastatin (previously sold under the trade name Mevacor, and now available as generic lovastatin).

Vytorin is drug that combines the use simvastatin and 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 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).

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 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.

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

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 with another protein called SREBP cleavage-activating protein (SCAP). 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, although this role has been disputed.

Degradation of reductase

Rising levels of sterols increase the susceptibility of the reductase enzyme to ER-associated 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.

Phosphorylation of reductase

Short-term regulation of HMG-CoA reductase is achieved by inhibition by 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 AMP-activated protein kinase, which also phosphorylates and inactivates 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 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 leptin, adiponectin, and other signaling molecules.

See also

• Oxidoreductase

External links

• Cholesterol Synthesis - has some good regulatory details
• Proteopedia HMG-CoA_Reductase - the HMG-CoA Reductase Structure in Interactive 3D