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Protein Science (2004), 13:1693-1697. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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FOR THE RECORD

Inhibition of the Class II HMG–CoA reductase of Pseudomonas mevalonii

Matija Hedl and Victor W. Rodwell

Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907-2063, USA

(RECEIVED December 22, 2003; FINAL REVISION March 9, 2004; ACCEPTED March 14, 2004)



Abstract

There are two structural classes of HMG–CoA reductase, the third enzyme of the mevalonate pathway of isopentenyl diphosphate biosynthesis—the Class I enzymes of eukaryotes and the Class II enzymes of certain eubacteria. Structural requirements for ligand binding to the Class II HMG–CoA reductase of Pseudomonas mevalonii were investigated. For conversion of mevalonate to HMG–CoA the –CH3, –OH, and –CH2COO– groups on carbon 3 of mevalonate were essential for ligand recognition. The statin drug Lovastatin inhibited both the conversion of HMG–CoA to mevalonate and the reverse of this reaction. Inhibition was competitive with respect to HMG–CoA or mevalonate and noncompetitive with respect to NADH or NAD+. Ki values were millimolar. The over 104-fold difference in statin Ki values that distinguishes the two classes of HMG–CoA reductase may result from differences in the specific contacts between the statin and residues present in the Class I enzymes but lacking in a Class II HMG–CoA reductase.

Keywords: HMG-CoA reductase; Class II HMG-CoA reductase; Pseudomonas mevalonii; isoprenoid biosynthesis; statin drug; Lovastatin

Reprint requests to: Victor W. Rodwell, Department of Biochemistry, Purdue University, 175 South University Street, West Lafayette, IN 47907-2063, USA; e-mail: vrodwell{at}purdue.edu; fax: (765) 494-7897.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03597504.


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