HMG-CoA reductase
From Wikipedia, the free encyclopedia
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| HMG-CoA reductase | |
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3-hydroxy-3-methylglutaryl-Coenzyme A reductase
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| Identifiers | |
| Symbol(s) | HMGCR |
| Entrez | 3156 |
| 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 first enzyme (EC 1.1.1.88) of the HMG-CoA reductase pathway, the metabolic pathway that produces cholesterol and various other biomolecules. Drugs which inhibit HMG-CoA reductase, known collectively as HMG-CoA reductase inhibitors (or "statins"), are used in to lower serum cholesterol as a means of reducing the risk for cardiovascular disease. These drugs include atorvastatin (Lipitor), pravastatin (Pravachol), and simvastatin (Zocor).
The CAS number for this type of the enzyme is [37250-24-1].
The gene for HMG-CoA reductase is located on the long arm of the fifth chromosome (5q13.3-14).
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[edit] 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 key, regulated 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].
[edit] Regulation
Regulation of HMG-CoA reductase is achieved at several levels: transcription, translation, degradation and phosphorylation.
[edit] 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.
[edit] Translation of mRNA
Translation of mRNA is inhibited by mevalonate derivatives and dietary cholesterol.
[edit] Degradation of reductase
Rising levels of sterols increases the susceptibility of the reductase enzyme to proteolysis. The protease that activates SREBP is also sensitive to levels of sterols.
[edit] Phosphorylation of reductase
Much like other key enzymes in biosynthetic pathways, HMG-CoA reductase is inhibited by phosphorylation (of Serine 872, in humans1). The protein kinase responsible for this is activated by a cyclic AMP cascade. This means that cholesterol synthesis does not occur if cellular ATP levels are low.
[edit] References
- 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(5): p. 819-830. PMID 10698924
- Berg, J.M., et al., Biochemistry. 5th ed. 2002, New York: W.H. Freeman. 1 v. (various pagings).
