SYNTHESIS OF VITAMIN B12 MODELS

维生素 B12 模型的合成

• 批准号: 3269790
• 负责人: PAUL DOWD
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3269790
• 关键词: biotransformation; catalyst; chemical models; chemical synthesis; cobalamin; enzyme complex; enzyme mechanism; glutamate decarboxylase; glutamates; isomerase; malonates; methylmalonyl coA epimerase; molecular cloning; nutrition related tag; stereochemistry; vitamin B12; vitamin B12 coenzyme

Vitamin B12, in the form of its coenzyme, is an obligatory cofactor in a series of twelve enzyme catalyzed reactions. The glutamate mutase, methyl- malonyl-CoA mutase and methylitaconate mutase enzymes are of outstanding interest because they catalyze carbon-skeleton rearrangements for which there have been no analogues in organic chemistry. The methylmalonyl-CoA to succinyl-CoA rearrangement is of crucial import in mammalian systems; it is the way the body converts propionate to succinate, leading into the main stream of biochemical metabolism. In this proposal, the mechanism by which these rearrangements occur will be explored using both model and enzymic systems. A new model for the methymalonyl-CoA system has been synthesized with an appended free radical trap to test for the occurrence of radical intermediates. This test will also be applied to the enzyme system. In addition, a new, synthetic malonate binding molecule will be used to study the reversibility of the model rearrangement. In order to facilitate the study of the function and structure of glutamate mutase, the gene will be cloned. Then, with adequate supplies of pure enzyme, mechanistic and structural studies will be initiated. Free radical and carbanion intermediates in the glutamate-methylaspartate rearrangement will be explored and a very successful Schiff base model will be developed. Surfactant-based models will be examined for their impact on our understanding of some unprecedented free radical migration reactions.

维生素B12，以其辅酶的形式，是一种必需的辅因子， 12个酶催化反应。 谷氨酸盐，甲基- 丙二酰辅酶A β和甲基衣康酸β酶具有显著的 因为它们催化碳骨架重排， 在有机化学中还没有类似物。 甲基丙二酰辅酶A 琥珀酰辅酶A重排在哺乳动物系统中至关重要; 这是身体将丙酸盐转化为琥珀酸盐的方式，导致 生化代谢的主流。 在该提案中， 这些重排发生将探讨使用模型和 酶系统 已经合成了甲基丙二酰-CoA系统的新模型， 附加自由基捕获器，以检测自由基的发生 中间体的 本试验也适用于酶系统。在 此外，一种新的合成丙二酸结合分子将用于研究 模型重排的可逆性。 为方便 通过对谷氨酸酯酶基因的结构和功能的研究， 克隆的 然后，有了足够的纯酶，机械和 将开始结构研究。 自由基和碳负离子 谷氨酸-甲基天冬氨酸重排中的中间体将是 探索和一个非常成功的席夫碱模型将开发。 基于表面活性剂的模型将检查其对我们的影响， 了解一些前所未有的自由基迁移反应。