Mechanistic Studies of New C-S Bond Formation Chemistries

该奖项由化学部生命过程化学项目资助波士顿大学刘平华博士研究麦角硫蛋白和卵硫醇生物合成中氧化C-S键的形成机制。硫醇分子在生物系统中扮演着许多重要的角色。麦角硫蛋白和卵硫醇生物合成中的氧化C-S键的形成(EgtB催化和OvoA催化)在2010年底和2011年初首次由Seebeck和他的同事报道。在对OvoA催化的初步研究中，刘小组又发现了这些酶的三种新的化学成分。在该奖项的支持下，他们将整合有机合成、分子生物学、生物信息学和酶学等不同学科的工具，进行详细的机械研究。我们的目标是在选定的氧化C-S成键机制选项中进行区分。然后，通过合成化学、稳态前动力学和光谱技术的组合，他们将捕获和表征一些建议的中间体。这项研究的信息将为这种新型C-S键形成的反应机理提供深入的见解。硫约占细胞干重的1%，为各种生物分子增加了相当大的官能度。麦角硫醚和卵硫醇中的硫醇-咪唑官能团使它们相对于其他自然存在的硫醇来说是独特的。因此，麦角硫氨酸被认为在细胞功能中扮演许多有益的角色。这项研究所获得的信息不仅将为C-S键形成化学(酶学的前沿之一)提供机制方面的见解，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)。拟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)将为培养高中生、本科生和研究生在化学和生物学方面的研究提供一个理想的机会。

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.