Mechanistic Studies of New C-S Bond Formation Chemistries

凭借这一奖项，化学学部生命过程化学项目将资助波士顿大学刘平华博士研究麦角硫因和卵黄硫醇生物合成中氧化C-S键形成的机制。含硫醇分子在生物系统中起着许多重要的作用。麦角硫因和卵硫醇生物合成（egtb催化和OvoA催化）中氧化C-S键的形成是由Seebeck及其同事在2010年底和2011年初首次报道的。在对ovoa催化的初步研究中，Liu小组发现了这些酶的另外三种新的化学反应。在该奖项的支持下，他们将通过整合不同学科的工具，包括有机合成、分子生物学、生物信息学和酶学，进行详细的机制研究。目的是区分选择的氧化C-S键形成机制的选择。然后，通过合成化学、预稳态动力学和光谱学技术的结合，他们将捕获并表征一些提议的中间体。该研究结果将为这种新型C-S键形成的反应机理提供新的见解。硫约占细胞干重的1%，为各种生物分子增加了相当大的功能。麦角硫因和卵硫醇中的硫-咪唑功能使它们相对于其他天然存在的硫醇具有独特性。因此，麦角硫因被认为在细胞功能中发挥了许多有益的作用。本研究获得的信息不仅将提供C-S键形成化学（酶学前沿之一）的机制见解，而且还将有助于相关领域的研究（例如，研究这些重要代谢物的生理作用）。所提议工作的跨学科性质（有机合成，分子生物学，生物信息学和酶学）将为培养高中学生，本科生和研究生在化学和生物学界面的研究提供理想的机会。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Pinghua Liu from Boston University to study the mechanism of the oxidative C-S bond formations in ergothioneine and ovothiol biosyntheses. Thiol-containing molecules play many important roles in biological systems. The oxidative C-S bond formations in ergothioneine and ovothiol biosyntheses (EgtB-catalysis and OvoA catalysis) were first reported in late 2010 and early 2011 by Seebeck and co-workers. In preliminary studies on OvoA-catalysis, the Liu Group discovered three more new chemistries of these enzymes. With support from this award, they will carry out detailed mechanistic studies by integrating tools from various disciplines, including organic synthesis, molecular biology, bioinformatics, and enzymology. The goals are to differentiate among selected oxidative C-S bond formation mechanistic options. Then, through a combination of synthetic chemistry, pre-steady state kinetics, and spectroscopy techniques, they will trap and characterize some of the proposed intermediates. Information from this study will provide insights into the mechanism of the reactions of this new type of C-S bond formation.Representing about 1% of cell dry weight, sulfur adds considerable functionality to a wide variety of biomolecules. The thiol-imidazole functionality in ergothioneine and ovothiol makes them unique relative to other naturally occurring thiols. As a result, ergothioneine is proposed to play many beneficial roles in cellular functions. Information gained in this study will not only provide mechanistic insights on C-S bond formation chemistries (one of the frontiers in enzymology), but also help studies in related areas (e.g., investigating the physiological roles of these important metabolites). The interdisciplinary nature of the proposed work (organic synthesis, molecular biology, bioinformatics and enzymology) will provide an ideal opportunity to train high school students, undergraduates, and graduate students for research at the interface of Chemistry and Biology.