CAREER: Spectroscopic/Computational Insights into the Biosynthesis and Reactivity of Adenosylcobalamin

职业：腺苷钴胺生物合成和反应性的光谱/计算见解

• 批准号: 0238530
• 负责人: Thomas Brunold
• 金额: $ 89.08万
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0238530&HistoricalAwards=false
• 关键词: CAREER; Spectroscopic; Computational; Insights; into

The B12 cofactor adenosylcobalamin has long fascinated chemists with its unparalleled structural complexity and unusual reactivity in biological systems, involving homolytic cleavage of the organometallic Co-C bond. The goals of this CAREER project are to develop molecular-level understanding of the mechanism by which the adenosyltransferase from Salmonella enterica catalyzes the Co-C bond formation and to explore the mechanism by which the adenosylcobalamin -dependent isomerase methylmalonyl-CoA mutase from Proprionibacterium shermanii accelerates the rate of homolytic Co-C bond cleavage by 12 orders of magnitude without significantly enhancing undesired Co-C bond heterolysis. These goals will be accomplished by using a combination of spectroscopic methods (electronic absorption, circular dichroism, magnetic circular dichroism, resonance Raman, and electron paramagnetic resonance) and computational techniques (density functional theory and combined quantum mechanics/molecular mechanics approaches) to study free and enzyme-bound adenosylcobalamin and derivatives thereof. The educational plan is to develop and implement a series of interactive projects aimed at guiding student exploration of key chemical concepts in symmetry, bonding, and inorganic electronic spectroscopy. The Kolb model, a well-researched student-centered teaching model, will serve as the framework for incorporating both spectroscopic data collection and Mathcad-based interactive projects into graduate and upper-level undergraduate classrooms. Research in the interdisciplinary field of bioinorganic spectroscopy readily facilitates the development of a collaborative learning environment, in which students with diverse backgrounds share and communicate their individual expertise. The linking of research to applied chemistry provides a template for students attempting to bridge the gap between classroom and laboratory settings. Through integration of research-oriented problems into the classroom, new techniques and exercises engendering student involvement in the teaching process will be developed. Together, the research and educational projects outlined in this project would foster the breadth of experience, depth of knowledge, and communication skills crucial to the development of young scientists. This project is supported by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Inorganic, Bioinorganic and Organometallic Chemistry Program in the Division of Chemistry in the Mathematical and Physical Sciences Directorate.

B12 辅因子腺苷钴胺素以其无与伦比的结构复杂性和生物系统中不寻常的反应性（涉及有机金属 Co-C 键的均裂）而长期吸引着化学家。该 CAREER 项目的目标是从分子水平上理解肠沙门氏菌的腺苷转移酶催化 Co-C 键形成的机制，并探索谢尔曼丙酸杆菌的腺苷钴胺素依赖性异构酶甲基丙二酸单酰辅酶 A 变位酶将均裂 Co-C 键裂解速率加快 12 的机制。 数量级，但不会显着增强不希望的 Co-C 键异质作用。这些目标将通过结合使用光谱方法（电子吸收、圆二色性、磁圆二色性、共振拉曼和电子顺磁共振）和计算技术（密度泛函理论和组合量子力学/分子力学方法）来研究游离和酶结合的腺苷钴胺素及其衍生物来实现。该教育计划旨在开发和实施一系列互动项目，旨在引导学生探索对称性、键合和无机电子光谱等关键化学概念。 Kolb 模型是一种经过充分研究的以学生为中心的教学模型，将作为将光谱数据收集和基于 Mathcad 的交互式项目纳入研究生和高年级本科生课堂的框架。生物无机光谱学跨学科领域的研究很容易促进协作学习环境的发展，在这种环境中，具有不同背景的学生可以分享和交流他们的个人专业知识。研究与应用化学的联系为试图弥合课堂和实验室环境之间差距的学生提供了一个模板。通过将研究型问题融入课堂，将开发新的技术和练习，使学生参与教学过程。该项目概述的研究和教育项目将共同培养对年轻科学家的发展至关重要的经验广度、知识深度和沟通技巧。 该项目得到了生物科学局分子和细胞生物科学司的分子生物物理学计划以及数学和物理科学局化学司的无机、生物无机和有机金属化学计划的支持。