REGULATION OF ISOPRENOID BIOSYNTHESIS IN RAT LIVER

这项建议的主要目标是阐明 控制甲氧戊酸在肝脏中的代谢分支途径。模型 “通量转移”的概念，该理论指出， 途径在大范围变化的速率中保持不变 胆固醇的生成将通过量化的水平直接检查 异戊烯基焦磷酸盐和法尼基焦磷酸盐。 一种来自甲氧戊酸的不明非甾醇产品已被证明 影响HMG-CoA还原酶活性的限速酶 甲氧戊酸生产。甲氧戊酸衍生非甾醇的可能性 产品还会影响分支点酶反式戊烯基转移酶和 角鲨烯合成酶将被检测。所遵守的任何法规的性质 将进行调查以确定转录、翻译或 这涉及到翻译后的机制。 甲氧戊酸的新陈代谢产生一种“丙烯化”的化合物 将对蛋白质进行研究。将尝试开发一种体外培养技术 仔细检查预烯基化反应的化验，重点是 鉴定修饰的蛋白质和修饰的功能 反应。

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.