Protein methyltransferases as a target class for drug discovery

Post-translational modifications of histones, the major protein components of chromatin, provide the mechanistic underpinning for epigenetic regulation of gene transcription. Among the enzymes that modify histones, the protein methyltransferases (PMTs) are particularly attractive as drug targets.A number of PMTs have been directly associated with the pathogenesis of diseases such as human cancers, inflammatory diseases, metabolic diseases, neurodegenerative diseases and other unmet medical needs of patients.The PMT target class is composed of two enzyme families: the protein lysine methyltransferases (PKMTs) and the protein arginine methyltransferases (PRMTs). All of the PMTs use a common, small-molecule cofactor, S-adenosyl-L-methionine (SAM), as the universal methyl donor for the enzymatic methylation of protein lysine and arginine side chains.The universal use of SAM by PMTs is reminiscent of the universal use of ATP by protein kinases, a well-established drug target class of enzymes. As for the ATP-binding pockets of kinases, the SAM-binding pockets of PMTs show substantial structural diversity in terms of both the amino acids that line the enzyme pockets and the conformation of ligands bound in the pockets of various PMTs, as revealed by X-ray crystallographic studies. These results suggest that the development of selective inhibitors of specific PMTs is achievable.Here, we review the biological, biochemical, medicinal chemical and structural biological data that together present the PMTs as a large, pathology-relevant, druggable target class for drug discovery. As for the ATP-binding pocket of kinases, we suggest that the SAM-binding pockets of PMTs provide a clear target for pharmacological modulation of selective PMT activity.