Abstract
The protein methyltransferases (PMTs) represent a large class of enzymes that catalyse the methylation of side chain nitrogen atoms of the amino acids lysine or arginine at specific locations along the primary sequence of target proteins. These enzymes play a key role in the spatio-temporal control of gene transcription by performing site-specific methylation of lysine or arginine residues within the histone proteins of chromatin, thus effecting chromatin conformational changes that activate or repress gene transcription. Over the past decade, it has become clear that the dysregulated activity of some PMTs plays an oncogenic role in a number of human cancers. Here we review research of the past decade that has identified specific PMTs as oncogenic drivers of cancers and progress toward the discovery and development of selective, small molecule inhibitors of these enzymes as precision cancer therapeutics.This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Highlights
The human protein methyltransferases (PMTs) comprise a large class of enzymes that catalyse the methylation of specific lysine or arginine amino acid side chains within target proteins [1]
A single PMT is responsible for multiple rounds of methylation of a specific lysine or arginine location, while in other cases different PMTs perform the distinct, sequential methylation reactions
In 2011, Richon et al [5] approached this question by focusing on amino acid sequences that formed the SAM binding pocket of proteins with experimentally verified enzymatic activity as either protein lysine methyltransferases (PKMTs) or protein arginine methyltransferases (PRMTs)
Summary
The human protein methyltransferases (PMTs) comprise a large class of enzymes that catalyse the methylation of specific lysine or arginine amino acid side chains within target proteins [1]. The two side chain nitrogen atoms of arginine can be unmethylated, monomethylated, symmetrically di-methylated or assymmetrically dimethylated Each of these states of methylation at specific amino acid locations can have distinct conformational consequences for the target protein. Chromosomal DNA is packaged as nucleosomes with intervening stretches of uncomplexed DNA as a mechanism of compacting approximately 2 m of DNA required for the complete human genome into the small volume of a eukaryotic cell nucleus [3] This highly compacted structure, creates steric barriers that restrict access of the transcriptional machinery to promoter regions of genes. The amplitude and cadence of these chromatin modifying activities determine the cellular programme of genes to be actively transcribed for any specific cell type at any specific time in the life of the cell These mechanisms are critical to a number of physiological processes, such as cell differentiation and maturation from pluripotent, stem cell-like progenitors. We will focus our attention on the progress made over the past decade to understand the role of dysregulated PMTs in human cancers and efforts towards the discovery and development of selective, small molecule inhibitors of these enzymes as a basis for precision cancer therapeutics
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