Functions of Carbon-Oxygen Hydrogen Bonding in Biological Methyl Transfer

获得这一奖项的生命过程化学项目资助密歇根大学的Raymond Trievel教授研究甲基CH-O氢键在S-腺苷蛋氨酸(ADOMet或SAM)依赖的甲基转移酶中起重要作用的命题。甲基转移酶是催化许多生物分子代谢的反应，以及通过蛋白质、DNA和RNA的甲基化而在细胞信号传递中催化反应的酶。此外，甲基转移酶与许多疾病有关，使其成为治疗癌症、心血管疾病、微生物感染和神经疾病的新药设计的有吸引力的靶点。最近的研究表明，转移的甲基在这些酶的活性部位形成了非常规的碳氧(CH-O)氢键。尽管生物大分子中存在CH-O氢键的假设已经存在了一段时间，但这些相互作用对生物过程的潜在贡献，特别是甲基转移，仍然没有得到很好的确定。这个项目的目标是通过实验和计算方法来表征这些氢键在甲基转移酶中的功能。这个项目将在生物化学、结构生物学和光谱学领域吸引本科生和研究生，在化学-生物学界面提供多学科的研究经验。它还将为学生提供在国家研究实验室进行复杂实验的机会。利用模型甲基转移酶，这些氢键在Adobe Met识别和甲基转移催化中的功能将通过结合酶学、结晶学、核磁共振光谱和计算方法的综合方法来研究。这些研究的结果将被用来开发一个概念性的框架，试图确定CH-O氢键在ADOMet依赖的甲基转移酶中的酶作用。在更广泛的背景下，预计这项工作将产生洞察力，导致对这些相互作用对酶催化和生物分子结构的贡献有更全面的了解。

With this award, the Chemistry of Life Processes Program is funding Professor Raymond Trievel at the University of Michigan to investigate the proposition that methyl CH---O hydrogen bonding plays an important role in S-adenosylmethionine (AdoMet or SAM)-dependent methyltransferases. Methyltransferases are enzymes that catalyze reactions in the metabolism of numerous biological molecules, as well as in cellular signaling through the methylation of proteins, DNA, and RNA. In addition, methyltransferases have been implicated in numerous diseases, making them attractive targets for the design of new drugs to treat cancer, cardio-vascular disease, microbial infections, and neurological disorders. Recent studies suggest that the transferred methyl group forms unconventional carbon-oxygen (CH---O) hydrogen bonds within the active sites of these enzymes. Although the existence of CH---O hydrogen bonds in biological macromolecules has been postulated for some time, the potential contributions of these interactions to biological processes, particularly methyl transfer, remain poorly defined. The goal of this project is to characterize the functions of these hydrogen bonds in methyltransferases using experimental and computational approaches. This project will engage both undergraduate and graduate students in the fields of biochemistry, structural biology, and spectroscopy, providing for a multi-disciplinary research experience at the chemistry-biology interface. It will also provide students with opportunities to perform sophisticated experiments at national research laboratories. Using model methyltransferases, the functions of these hydrogen bonds in AdoMet recognition and methyl transfer catalysis will be examined using an integrated approach combining enzymology, crystallography, NMR spectroscopy, and computational methods. The results of these studies will be used to develop a conceptual framework that seeks to define the enzymatic roles of CH---O hydrogen bonding in AdoMet-dependent methyltransferases. In the broader context, it is envisioned that this work will yield insights that lead to a more general understanding of the contributions of these interactions to enzyme catalysis and biomolecular structure.