Functions of Carbon-Oxygen Hydrogen Bonding in Biological Methyl Transfer

有了这个奖项，生命过程计划的化学正在资助密歇根大学的Raymond Trievel教授研究甲基CH-O氢键在S-腺苷甲硫氨酸（SAM）依赖性甲基转移酶中发挥重要作用的命题。 甲基转移酶是在许多生物分子的代谢中催化反应的酶，以及通过蛋白质、DNA和RNA的甲基化在细胞信号传导中催化反应的酶。 此外，甲基转移酶与许多疾病有关，使其成为设计治疗癌症、心血管疾病、微生物感染和神经系统疾病的新药的有吸引力的靶标。 最近的研究表明，转移的甲基在这些酶的活性位点内形成非常规的碳-氧（CH--O）氢键。虽然在生物大分子中存在CH-O氢键已经被假定了一段时间，但这些相互作用对生物过程的潜在贡献，特别是甲基转移，仍然很难确定。 这个项目的目标是使用实验和计算方法来表征甲基转移酶中这些氢键的功能。 该项目将吸引生物化学，结构生物学和光谱学领域的本科生和研究生，为化学-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。使用模型甲基转移酶，这些氢键的功能，在AMMET识别和甲基转移催化将使用一个综合的方法相结合的酶学，晶体学，NMR光谱学和计算方法进行检查。 这些研究的结果将被用来开发一个概念框架，旨在定义的酶的作用，CH-O氢键的甲基转移酶依赖于蛋氨酸。 在更广泛的背景下，预计这项工作将产生的见解，导致更普遍的理解这些相互作用的酶催化和生物分子结构的贡献。

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.