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.

该提案的主要目的是研究第一个特定酶 在肝脏中的胆固醇生物合成途径中 合成酶，以了解其调节的机制。 现在可以实现这个目标，因为我们最近隔离，纯化和 获得的大鼠肝鳞状合成酶的部分蛋白序列 大鼠和人类酶的蛋白质以及cDNA克隆。 反过来，这将使我们能够克隆并研究 酶。 大鼠肝松弛烯合成酶调节的机制 转录，翻译和蛋白质水平将在较宽的情况下检查 胆固醇发生的变化。 变体的贡献 这种酶对转移的共同中间体的活性， 特异性的反式氟磷酸二磷酸盐和非固醇 将检查产品（通量转移假设）。 小矛烯的5'Franking区域的检查和比较 在该途径中的其他已知调节酶的合成酶基因可能 解释甲龙酸盐分支途径的复杂调节。 克隆和对小矛烯合酶的调节的理解， 胆固醇生物合成途径中最具体的酶，可能 允许开发将与之互动的化合物并更改 这种酶的活性，因此可以用作胆固醇 降低药物。