HMG-CoA reductase
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HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR) is the first enzyme (EC 1.1.1.88 (http://www.expasy.org/cgi-bin/nicezyme.pl?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 gene for HMG-CoA reductase is located on the long arm of the fifth chromosome (5q13.3-14).
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Regulation
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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. 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 mevalonate derivatives and dietary cholesterol.
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.
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.
External link
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).de:HMG-CoA-Reduktase