NOVEL INHIBITORS OF CHOLESTEROL BIOSYNTHESIS

新型胆固醇生物合成抑制剂

• 批准号: 3337141
• 负责人: THOMAS A SPENCER
• 金额: $ 12.84万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-08-01 至 1986-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3337141
• 关键词: antihypercholesterolemic agent; atherosclerosis; diol; lanosterol; liver; squalene; tissue /cell culture; triterpenes

Research initiated by the discovery that 4, 4, 10Beta-trimethyl-transdecal-3Beta-ol (TMD) is an effective inhibitor of cholesterol biosynthesis at the oxidosqualene cyclase stage will be continued. This finding has enabled an ongoing investigation of the biochemistry of squalene 2,3(Sapproximately);22(Sapproximately),23-dioxide and related dioxygenated triterpenoids and steroids. Of particular potential significance is the finding that 24(Sapproximately),25-epoxycholesterol is formed in the normal course of sterol biosynthesis by the enzymes in rat liver homogenate. It will be determined whether this epoxide occurs in intact tissue and, if so, what its biochemical properties and metabolic fate are. Greater understanding of the natural mechanisms of cholesterol formation and regulation may result from this research, and such understanding will eventually be important in achieving control of atherosclerosis. The inhibition of cholesterol biosynthesis by TMD has also proved to be valuable in collaborative studies of cell replication, and these investigations will continue. The effect of substances structurally related to TMD on cholesterol biosynthesis will be studied in order to elucidate the structural requirements for inhibition and to develop additional inhibitors which will be useful as research tools. TMD and related inhibitors of oxidosqualene cyclase will also be used to try to gain insight into the structure and mechanism of this important enzyme through efforts at purification by affinity chromatography and at affinity labelling of the active side.

发现4、4， 10BETA-三甲基 - Transdecal-3beta-Ol（TMD）是有效的抑制剂 氧化盐环酶阶段的胆固醇生物合成将是 持续。 这一发现使对 Spolene的生物化学2,3（sapproxiail）； 22（sapproxiale），23-二氧化物 以及相关的二氧化三萜和类固醇。 特别 潜在的意义是发现 24（sapproxiale），在正常过程中形成25-蛋白胆固醇 大鼠肝匀浆中的酶生物合成。 这将是 确定这种环氧是否发生在完整的组织中，如果是的， 它的生化特性和代谢命运是。 更大的理解 胆固醇形成和调节的自然机制可能 这项研究的结果，这种理解最终将是 对于控制动脉粥样硬化的控制很重要。 抑制 TMD的胆固醇生物合成也已被证明是有价值的 细胞复制的协作研究，这些研究将 继续。 与TMD结构相关物质对物质的影响 将研究胆固醇生物合成，以阐明 抑制的结构要求并开发其他抑制剂 作为研究工具，这将是有用的。 TMD和相关抑制剂 氧化盐环酶也将用于尝试洞悉 通过努力的这种重要酶的结构和机制 通过亲和力色谱和亲和力标记纯化 主动方面。