Functions of Carbon-Oxygen Hydrogen Bonding in Biological Methyl Transfer

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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 C-H-oxygen hydrogen bonding plays an important role in S-adenosylmethionine (AdoMet or SAM)-dependent lysine methyltransferases. AdoMet-dependent methylation is a ubiquitous reaction in biology and has integral roles in metabolism and signal transduction, particularly with respect to DNA and histone lysine methylation in epigenetic gene regulation. Unconventional C-H---O hydrogen bonds have been reported to coordinate the AdoMet methyl group in the active sites of lysine methyltransferases, but their role in methyl transfer has remained poorly understood. Using the lysine methyltransferase SET7/9 as a model enzyme, this project will examine the functions of these hydrogen bonds in AdoMet recognition and catalysis using an integrated approach combining enzymology, X-ray crystallography, NMR spectroscopy, and unnatural amino acid mutagenesis. The results of these studies will provide a conceptual framework that defines the enzymatic roles of carbon-oxygen hydrogen bonding in lysine methyltransferases as well as other classes of AdoMet-dependent methyltransferases that also exhibit methyl carbon-oxygen hydrogen bonding. In the broader context, it is envisioned that this work will provide insights that lead to a more general understanding of the functional importance of C-H---O hydrogen bonding in biological methyl transfer. With respect to training/educational impact, this project will engage both undergraduate and graduate students in the fields of chemical biology, structural biology and biophysics/spectroscopy, providing for a stimulating, multi-disciplinary research experience at the Chemistry-Biology interface. The PI will continue to work to bring women and students from traditionally underrepresented groups into the research laboratory.