Inactivation of hydroxymethylglutaryl-CoA reductase from yeast by coenzyme A disulfide.
The time-dependent inactivation of hydroxymethylglutaryl-CoA reductase from yeast by solutions of hydroxymethylglutaryl-CoA and CoASH is due to the rapid inactivation of the enzyme by oxidized CoA (CoA disulfide) present at trace levels in solutions of hydroxymethylglutaryl-CoA and CoASH. Solutions of hydroxymethylglutaryl-CoA or CoASH incubated for 1.5 h with 10 mM dithiothreitol at pH 7.0, 22 degrees C, do not inactivate the enzyme. Inactivation of hydroxymethylglutaryl-CoA reductase is rapid and complete at concentrations of CoA disulfide comparable to those measured in solutions of hydroxymethylglutaryl-CoA and CoASH. Inactivation of the enzyme by CoA disulfide may be reversed by treating the inactive enzyme with 10 mM dithiothreitol at pH 7.0 Both the inactivation of the enzyme by CoA disulfide and reactivation by dithiothreitol are inhibited by hydroxymethylglutaryl-CoA. Other disulfides such as Ellman's reagent and glutathione disulfide also inactivate the enzyme. A thio-disulfide exchange reaction with a sulfhydryl group on the enzyme forming a mixed disulfide or an intramolecular protein disulfide could account for the enzyme inactivation. The normal function of the sulfhydryl group involved in the inactivation of the enzyme is unknown.
D003065:Coenzyme A / Q000494:pharmacology*; D004229:Dithiothreitol / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D010084:Oxidation-Reduction; D012441:Saccharomyces cerevisiae / Q000201:enzymology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C017145:coenzyme A disulfide; D003065:Coenzyme A; D004229:Dithiothreitol