Investigating the Functional Impacts of Tetrel Bonding in the Reaction Mechanism of Methyltransferases and Screening of Peptidomimetic Inhibitors


May 2023

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While protein methyltransferases have important roles in many biological processes such as gene regulation and RNA processing, their dysregulation has been implicated in the progression of a number of diseases such as cancers and neurological conditions. These enzymes catalyze the methylation of lysine and arginine residues of target proteins using the cofactor and methyl donor, S-adenosyl methionine (SAM). A study of crystal structures of SAM-bound methyltransferases, along with computational studies using small molecule models, have revealed the presence of a type of non-covalent interaction termed a tetrel bond between the SAM methyl group and electron donating atoms of the target substrate. Since the tetrel-bonded complex in methyltransferase active site precedes the transition state in the SN2 methylation pathway, in this project it was hypothesized that methyltransferase active site promotes the formation of the tetrel-bonded complex, which is fundamental to the catalytic role of these enzymes. Using an optimized coupled fluorescent kinetic assay and site-directed mutagenesis to change a tyrosine residue to a phenylalanine in the active site of a model methyltransferase, SET7/9, a hydrogen bond which is believed to hold the tetrel- bonded complex in the correct orientation was removed, resulting in a 15-fold decrease in enzyme activity. Moreover, using this optimized fluorescence-based assay, ~80 peptidomimetic compounds were screened for inhibition of SET7/9, with the most potent compound, B21-2, having an IC50 value of 5.2 μM. Through understanding tetrel bonding and the use of lead compounds discovered, inhibitors may be designed to exploit unique interactions yielding potent and selective inhibitors for these enzymes.



Chemistry, Biochemistry