Inhibition of the class II HMG-CoA reductase of Pseudomonas mevalonii.
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.
Hedl
Matija
M
Department of Biochemistry, Purdue University, 175 South University Street, West Lafayette, IN 47907-2063, USA. vrodwell@purdue.edu
Rodwell
Victor W
VW
D004926:Escherichia coli / Q000235:genetics; D015870:Gene Expression; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015394:Molecular Structure; D011549:Pseudomonas / Q000201:enzymology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid