The structure of the catalytic portion of human HMG-CoA reductase

Eva S. Istvan, Johann Deisenhofer

Research output: Contribution to journalReview articlepeer-review

106 Scopus citations

Abstract

In higher plants, fungi, and animals isoprenoids are derived from the mevalonate pathway. The carboxylic acid mevalonate is formed from acetyl-CoA and acetoacetyl-CoA via the intermediate 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). The four-electron reduction of HMG-CoA to mevalonate, which utilizes two molecules of NADPH, is the committed step in the biosynthesis of isoprenoids. This reaction is catalyzed by HMG-CoA reductase (HMGR). The activity of HMGR is controlled through synthesis, degradation and phosphorylation. The human enzyme has also been targeted successfully by drugs, known as statins, in the clinical treatment of high serum cholesterol levels. The crystal structure of the catalytic portion of HMGR has been determined recently with bound reaction substrates and products. The structure illustrates how HMG-CoA and NADPH are recognized and suggests a catalytic mechanism. Catalytic portions of human HMGR form tight tetramers, explaining the influence of the enzyme's oligomeric state on the activity and suggesting a mechanism for cholesterol sensing. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)9-18
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1529
Issue number1-3
DOIs
StatePublished - Dec 15 2000

Keywords

  • 3-Hydroxy-3-methylglutaryl coenzyme A
  • Cholesterol biosynthesis
  • Enzyme mechanism
  • Nicotinamide adenine dinucleotide phosphate
  • Oxidoreductase

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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