The Role of Tetrel Bonding in the Reaction Mechanism of Methyltransferases

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With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Drs. Raymond Trievel of the University of Michigan - Ann Arbor and Allison Stelling of UT-Dallas are studying an important category of enzymes known as methyltransferases. Methyltransferases are ubiquitous enzymes that play fundamental roles in the metabolism of numerous biological molecules, as well as in cell signaling and gene regulation through methylation of proteins, DNA, and RNA. In addition, methyltransferases have been implicated in numerous diseases, rendering them important targets for the design of new modulators to study their functional significance and signaling roles in biology and their dysfunction in abnormal biology or disease (relevant to cancer, cardiovascular disease, some neurological disorders, and microbial viral infections including COVID-19). Recent studies have revealed that the methyl transfer reaction catalyzed by these enzymes occurs through an unconventional type of interaction called a tetrel bond. The existence of tetrel bonds in biological macromolecules has only recently been discovered, and the contributions of these interactions to biological processes, particularly methyl transfer, remain poorly understood. The goal of this project is to characterize the functions of the tetrel bonds in methyltransferases using experimental and computational approaches. The knowledge derived from these studies will potentially inform the development of new methyltransferase linhibitors. This project will engage both undergraduate and graduate students in research in the fields of biochemistry, biophysics, structural biology and spectroscopy, affording multi-disciplinary training at the chemistry-biology interface.Methylation is a ubiquitous reaction in biology that plays a central role in the metabolism of many biological molecules, including amino acids, carbohydrates, lipids, hormones, and metabolites. In addition, methylation represents a prominent covalent modification in proteins, DNA, and RNA, which has been implicated in signal transduction and gene regulation. Most methylation reactions are catalyzed by S-adenosylmethionine (AdoMet)-dependent methyltransferases via an SN2 transfer of the AdoMet methyl group to the acceptor substrate. A recent survey of crystal structures of methyltransferases bound to AdoMet and various ligands has revealed that the AdoMet methyl group engages in tetrel bonding, a type of sigma antibonding orbital interaction similar to halogen bonding. Prior computational studies utilizing small molecule models have demonstrated that tetrel bonding between the methyl carbon atom and the nucleophilic atom represents an intermediate preceding the transition state in the SN2 reaction pathway. The discovery of tetrel bonding between the AdoMet methyl carbon atom and various ligands in methyltransferase active sites implies that this interaction is fundamental to the catalytic mechanism of these enzymes. Building on these observations, the aims of this proposal are to: 1) determine the functions of AdoMet methyl tetrel bonding in catalysis and 2) characterize the effects of methyl tetrel bonding on the AdoMet methyl vibrational modes. The functional importance of these interactions will be investigated in detail using a model methyltransferase and an interdisciplinary approach combining biochemistry, spectroscopy, crystallography, and computational chemistry. Taken together, these studies aim to elucidate the mechanism by which tetrel bonding between the AdoMet methyl group and the nucleophile facilitates methyl transfer.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.