Functions of Carbon-Oxygen Hydrogen Bonding in Biological Methyl Transfer

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

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.