The major objective of this proposal is to elucidate the mechanisms which control the branched pathway of mevalonate metabolism in liver. The model of """"""""flux diversion"""""""" which states that the levels of intermediates in the pathway are held constant during wide variations in the rates of cholesterogenesis will be directly examined by quantitating the levels of isopentenyl pyrophosphate and farnesyl pyrophosphate. An unidentified nonsterol product derived from mevalonate has been shown to influence the activity of HMG-CoA reductase, the rate limiting enzyme of mevalonate production. The possibility that mevalonate derived nonsterol products also affect the branchpoint enzymes trans prenyltransferase and squalene synthase will be examined. The nature of any regulation observed will be investigated to determine if transcriptional, translational, or posttranslational mechanisms are involved. The metabolism of mevalonate to generate a compound which """"""""prenylates"""""""" proteins will be investigated. Attempts will be made to develop an in vitro assay to closely examine the prenylation reaction, with emphasis on identifying the proteins modified and the function of the modification reaction.
