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Protein family review

The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases

Jon A Friesen1* and Victor W Rodwell2

Author Affiliations

1 Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA

2 Department of Biochemistry, Purdue University, 175 South University Street, West Lafayette, IN 47907-2063, USA

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Genome Biology 2004, 5:248  doi:10.1186/gb-2004-5-11-248

Published: 1 November 2004

Abstract

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase catalyzes the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids. The enzyme is found in eukaryotes and prokaryotes; and phylogenetic analysis has revealed two classes of HMG-CoA reductase, the Class I enzymes of eukaryotes and some archaea and the Class II enzymes of eubacteria and certain other archaea. Three-dimensional structures of the catalytic domain of HMG-CoA reductases from humans and from the bacterium Pseudomonas mevalonii, in conjunction with site-directed mutagenesis studies, have revealed details of the mechanism of catalysis. The reaction catalyzed by human HMG-CoA reductase is a target for anti-hypercholesterolemic drugs (statins), which are intended to lower cholesterol levels in serum. Eukaryotic forms of the enzyme are anchored to the endoplasmic reticulum, whereas the prokaryotic enzymes are soluble. Probably because of its critical role in cellular cholesterol homeostasis, mammalian HMG-CoA reductase is extensively regulated at the transcriptional, translational, and post-translational levels.