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.
