New substrates and inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase.

Methyl (RS)-5-bromo-3-hydroxy-3-methyl-pentanoate was prepared by bromination of methyl mevalonate and used for the formation of 4-carboxy-3-hydroxy-3-methylbutyl thioether derivatives by reaction with N-octanoyl-cysteamine, pantetheine, phosphopantetheine and coenzyme A. These thiols were also converted to the (RS)-3-hydroxy-3-methylglutaryl thioester derivatives. The thioesters formed with pantetheine and phosphopantetheine are substrates of 3-hydroxy-3-methylglutaryl-CoA reductase; Km and V values are similar to those of the superior CoA-derivative. The corresponding thioether derivatives in which the oxygen next to sulfur of the substrates is replaced by hydrogen, are inhibitors of the reductase. The inhibition is competitive with 3-hydroxy-3-methylglutaryl-CoA varied, and noncompetitive with NADPH varied. For each of the corresponding pairs of thioester and thioether derivatives Km (substrate) is nearly identical with Ki (inhibitor). The specificity and stereospecificity of the inhibitor action are also shown.