|External IDs||GeneCards: |
|Gene Ontology||AmiGO / QuickGO|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
|PDB structures||RCSB PDB PDBe PDBsum|
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 22.214.171.124; NADPH-dependent, EC 126.96.36.199) 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, which is considered, by those who accept the standard lipid hypothesis, 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.
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:
- a conserved N-terminal sterol-sensing domain (SSD, amino acid interval: 88–218). The related SSD of SCAP has been shown to bind cholesterol.
- 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 (amino acids 522–574). This does not affect any of the aforementioned domains.
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. [§ 1]
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.
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 AMP-activated protein kinase, which responds to an increase in AMP concentration, and also to leptin
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 of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.
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 after controlled proteolytic processing. When SREBP is inactive, it is bound to the ER or nuclear membrane with another protein called SREBP cleavage-activating protein (SCAP). SCAP senses low cholesterol concentration and transports SREBP to the Golgi membrane where a consecutive proteolysis by S1P and S2P cleaves SREBP into an active nuclear form, nSREBP. nSREBPs migrate to the nucleus and activate transcription of SRE-containing genes. The nSREBP transcription factor is short-lived. When cholesterol levels rise, Insigs retains the SCAP-SREBP complex in the ER membrane by preventing its incorporation into COPII vesicles.
Translation of mRNA is inhibited by a mevalonate derivative, which has been reported to be the isoprenoid farnesol, although this role has been disputed.
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 are thought to sense increased cholesterol levels (direct sterol binding to the SSD of HMG-CoA reductase has not been demonstrated). Lysine residues 89 and 248 can become ubiquinated by ER-resident E3 ligases. The identity of the multiple E3 ligases involved in HMG-CoA degradation is controversial, with suggested candidates being AMFR, Trc8, and RNF145 The involvement of AMFR and Trc8 has been contested.
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.
- ↑ "Entrez Gene: HMGCR 3-hydroxy-3-methylglutaryl-Coenzyme A reductase".
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- ↑ Lindgren V, Luskey KL, Russell DW, Francke U (December 1985). "Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes". Proceedings of the National Academy of Sciences of the United States of America. 82 (24): 8567–71. Bibcode:1985PNAS...82.8567L. doi:10.1073/pnas.82.24.8567. PMC 390958. PMID 3866240.
- ↑ Brown MS, Radhakrishnan A, Goldstein JL (August 2017). "Retrospective on Cholesterol Homeostasis: The Central Role of Scap". Annual Review of Biochemistry. doi:10.1146/annurev-biochem-062917-011852. PMC 5828883. PMID 28841344.
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- ↑ "Is there a "best" statin drug?". The Johns Hopkins Medical Letter Health After 50. 15 (11): 4–5. January 2004. PMID 14983817.
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- ↑ Sun LP, Seemann J, Goldstein JL, Brown MS (April 2007). "Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins". Proceedings of the National Academy of Sciences of the United States of America. 104 (16): 6519–26. Bibcode:2007PNAS..104.6519S. doi:10.1073/pnas.0700907104. PMC 1851663. PMID 17428919.
- ↑ Sun LP, Li L, Goldstein JL, Brown MS (July 2005). "Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro". The Journal of Biological Chemistry. 280 (28): 26483–90. doi:10.1074/jbc.M504041200. PMID 15899885.
- ↑ Meigs TE, Roseman DS, Simoni RD (April 1996). "Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation by the nonsterol mevalonate metabolite farnesol in vivo". The Journal of Biological Chemistry. 271 (14): 7916–22. doi:10.1074/jbc.271.14.7916. PMID 8626470.
- ↑ Meigs TE, Simoni RD (September 1997). "Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase". Archives of Biochemistry and Biophysics. 345 (1): 1–9. doi:10.1006/abbi.1997.0200. PMID 9281305.
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- Cholesterol Synthesis - has some good regulatory details
- Proteopedia HMG-CoA_Reductase - the HMG-CoA Reductase Structure in Interactive 3D