Inhibition of the class II HMG-CoA reductase of Pseudomonas mevalonii.

Department of Biochemistry, Purdue University, 175 South University Street, West Lafayette, IN 47907-2063, USA. vrodwell@purdue.edu

Protein science : a publication of the Protein Society 2004 Jun

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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 -CH(3), -OH, and -CH(2)COO(-) 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(+). K(i) values were millimolar. The over 10(4)-fold difference in statin K(i) 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.

Citation

Matija Hedl, Victor W Rodwell. Inhibition of the class II HMG-CoA reductase of Pseudomonas mevalonii. Protein science : a publication of the Protein Society. 2004 Jun;13(6):1693-7