METABOLIC REGULATION OF RAT HEPATIC FLUX OF ISOPRENOIDS

类异戊二烯类化合物大鼠肝通量的代谢调节

• 批准号: 3367647
• 负责人: ISHAIAHU SHECHTER
• 金额: $ 23.27万
• 依托单位: ELEANOR ROOSEVELT INST FOR CANCER RES
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-06-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3367647
• 关键词: cholesterol; complementary DNA; enzyme induction /repression; enzyme mechanism; farnesyl compound; genetic promoter element; genetic regulation; genetic transcription; human genetic material tag; hydrocarbon oxidoreductase; immunoprecipitation; isoprenoid; laboratory rat; liver metabolism; molecular cloning; nucleic acid sequence; protein metabolism; radiotracer; squalene; steroid biosynthesis; structural genes

The main objective of this proposal is to study the first specific enzyme in the cholesterol biosynthetic pathway in the liver, squalene synthetase, in order to understand the mechanisms of its regulation. This objective is now attainable since we recently isolated, purified and obtained partial protein sequences of the rat liver squalene synthetase protein as well as cDNA clones for both the rat and the human enzymes. This, in turn, will enable us to clone and study the regulation of the enzyme. The mechanisms of regulation of rat hepatic squalene synthetase at the transcription, translation and protein level will be examined under wide variations of cholesterogenesis. The contribution of the variations of the activity of this enzyme to the diversion of common intermediates, specifically trans-farnesyl pyrophosphate, to sterol and nonsterol products (the flux diversion hypothesis) will be examined. Examination and comparison of 5'flanking regions of the squalene synthetase gene to other known regulatory enzymes in this pathway may explain the complex regulation of the mevalonate branched pathway. Cloning and the understanding of the regulation of squalene synthetase, the most specific enzyme in the cholesterol biosynthetic pathway, may allow the development of compounds that will interact with, and change the activity of this enzyme and therefore, may serve as cholesterol lowering drugs.

本课题的主要目的是研究第一种特异性酶