FEEDBACK-REGULATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE IN SACCHAROMYCES-CEREVISIAE

In eukaryotic cells all isoprenoids are synthesized from a common prec ursor, mevalonate. The formation of mevalonate from 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) is catalyzed by HMG-CoA reductase and is the first committed step in isoprenoid biosynthesis. In mammalian cel ls, synthesis of HMG-CoA reductase is subject to feedback regulation a t multiple molecular levels. We examined the state of feedback regulat ion of the synthesis of the HMG-CoA reductase isozyme encoded by the y east gene HMG1 to examine the generality of this regulatory pattern. I n yeast, synthesis of Hmg1p was subject to feedback regulation. This r egulation of HMG-CoA reductase synthesis was independent of any change in the level of HMG1 mRNA. Furthermore, regulation of Hmg1p synthesis was keyed to the level of a nonsterol product of the mevalonate pathw ay. Manipulations of endogenous levels of several isoprenoid intermedi ates, either pharmacologically or genetically, suggested that mevalona te levels may control the synthesis of Hmg1p through effects on transl ation.