Protein family review

This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.

Authors:

Jon A Friesen¹ and Victor W Rodwell²

¹Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
²Department of Biochemistry, Purdue University, 175 South University Street, West Lafayette, IN 47907-2063, USA

Correspondence:

Jon A Friesen.

Email:

jfriese@ilstu.edu

Read the full article

Subscribers to GenomeBiology may view the full version of this review article online at http://genomebiology.com/2004/5/11/248

Published:

1 November 2004

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

Summary

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.

Frontiers

Several basic unresolved questions concern how phosphorylation controls the catalytic activity of HMGRs; solution of the structures of phosphorylated HMGRs should reveal more of the precise mechanism. The protein kinases, phosphatases, and signal-transduction pathways that participate in short-term regulation of HMGR activity are yet to be elucidated. Finally, the physiological roles served by the multiple ways in which HMGR is regulated require clarification. On the medical side, continuing intense competition between drug companies for a share of the lucrative worldwide market for hypercholesterolemic agents should result in new statin drugs with modified pharmacodynamic and metabolic properties that not only lower plasma cholesterol levels more effectively but more importantly minimize undesirable side effects.

Schematic representation of the human hmgr gene and the human HMGRH and P. mevalonii HMGRP proteins

Structures of lovastatin, a statin drug that competitively inhibits HMGR, and of HMG-CoA