Histone methylation plays an important regulatory role in chromatin restructuring and RNA transcription. Arginine methylation that is enzymatically catalyzed by the family of protein arginine methyltransferases (PRMTs) can either activate or repress gene expression depending on cellular contexts. Given the strong correlation of PRMTs with pathophysiology, great interest is seen in understanding molecular mechanisms of PRMTs in diseases and in developing potent PRMT inhibitors. Herein, we reviewed key research advances in the study of biochemical mechanisms of PRMT catalysis and their relevance to cell biology. We highlighted how a random binary, ordered ternary kinetic model for PRMT1 catalysis reconciles the literature reports and endorses a distributive mechanism that the enzyme active site utilizes for multiple turnovers of arginine methylation. We discussed the impacts of histone arginine methylation and its biochemical interplays with other key epigenetic marks. Challenges in developing small-molecule PRMT inhibitors were also discussed.

Protein post-translational modifications (PTMs) in eukaryotic cells play important roles in the regulation of functionalities of the proteome and in the tempo-spatial control of cellular processes. Most PTMs enact their regulatory functions by affecting the biochemical properties of substrate proteins such as altering structural conformation, protein–protein interaction, and protein–nucleic acid interaction. Amid various PTMs, arginine methylation is widespread in all eukaryotic organisms, from yeasts to humans. Arginine methylation in many situations can drastically or subtly affect the interactions of substrate proteins with their partnering proteins or nucleic acids, thus impacting major cellular programs. Recently, arginine methylation has become an important regulator of the formation of membrane-less organelles inside cells, a phenomenon of liquid–liquid phase separation (LLPS), through altering π-cation interactions. Another unique feature of arginine methylation lies in its impact on cellular physiology through its downstream amino acid product, asymmetric dimethylarginine (ADMA). Accumulation of ADMA in cells and in the circulating bloodstream is connected with endothelial dysfunction and a variety of syndromes of cardiovascular diseases. Herein, we review the current knowledge and understanding of protein arginine methylation in regards to its canonical function in direct protein regulation, as well as the biological axis of protein arginine methylation and ADMA biology.

Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 (HAT1) is among the first histone acetyltransferase (HAT) enzymes that were discovered in the mid‐1990s; however, it remains one of the poorly studied enzymes in comparison with the other HATs. Although HAT1 has been linked to various disease states, no inhibitors have been reported to target HAT1. Here, we designed a set of peptide‐CoA conjugates as bisubstrate inhibitors of HAT1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a low Ki value of 1.1 nM for HAT1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism of HAT1 catalysis. Creating these submicromolar inhibitors offers mechanistic tools to better understand how HAT1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy.

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