Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase and citrate synthase by sulfoxides and sulfones of substrate-analogue CoA-thioether derivatives.
Sulfoxides and sulfones were prepared by specific oxidation of 3-hydroxy-3-methylglutaryl-CoA-analogue CoA-thioether derivatives and their kinetic properties were determined with 3-hydroxy-3-methylglutaryl-CoA reductase. The oxidized CoA-thioether derivatives with a hydroxyl group at C3 were powerful competitive inhibitors, their Ki values being much smaller than the Km for 3-hydroxy-3-methylglutaryl-CoA. Sulfoxides and sulfones of substrate analogues of citrate synthase were also prepared. When tested in the appropriate reaction with citrate synthase, the sulfoxide and sulfone derivatives were competitive inhibitors, but their Ki values were greater than the Km values of the corresponding unmodified substrates.
Karl
R M
RM
Institut für Physiologische Chemie, Technischen Universität München, Germany.
Hupperich
M
M
Thomer
A
A
Eggerer
H
H
D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors*; D003065:Coenzyme A / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D010084:Oxidation-Reduction; D013379:Substrate Specificity; D013440:Sulfides / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013454:Sulfoxides / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013440:Sulfides; D013450:Sulfones; D013454:Sulfoxides; D002950:Citrate (si)-Synthase; D003065:Coenzyme A