New Substrates and Inhibitors of 3-Hydroxy-3-methylglutaryl-CoA Reductase

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Abstract
Methyl (RS)-5-bromo-3-hydroxy-3-methylpentanoate 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-octanoylcysteamine, pantetheine, phosphopantetheine and CoA. These thiols were also converted to the (RS)-3-hydroxy-3-methylglutaryl [HMG] thioester derivatives. The thioesters formed with pantetheine and phosphopantetheine are substrates of [rat liver] HMG-CoA reductase; Km and Vmax values are similar to those of the superior CoA-derivative. The corresponding thioether derivatives in which the O next to S of the substrates is replaced by H, are inhibitors of the reductase. The inhibition is competitive with HMG-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.

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