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

B12辅因子腺苷钴胺素以其无与伦比的结构复杂性和在生物系统中不寻常的反应性长期吸引着化学家，涉及有机金属Co-C键的均裂。该CAREER项目的目标是发展对来自肠道沙门氏菌的腺苷转移酶催化Co-C键形成的机制的分子水平理解，并探索来自谢氏Proprionibacterium shermanii的腺苷钴胺素依赖性异构酶甲基丙二酰辅酶A β将均裂Co-C键裂解速率加速12个数量级而不显著增强不期望的Co-C键异裂的机制。这些目标将通过使用光谱方法（电子吸收、圆二色性、磁性圆二色性、共振拉曼和电子顺磁共振）和计算技术（密度泛函理论和结合的量子力学/分子力学方法）的组合来研究游离的和酶结合的腺苷钴胺素及其衍生物来实现。教育计划是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学中的关键化学概念。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设置之间的差距的学生提供了一个模板。通过将面向研究的问题纳入课堂，将开发新的技术和练习，使学生参与教学过程。该项目中概述的研究和教育项目将共同促进对青年科学家发展至关重要的经验广度、知识深度和沟通技能。 该项目由生物科学理事会分子和细胞生物科学部的分子生物物理学计划以及数学和物理科学理事会化学部的无机，生物无机和有机化学计划支持。

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.