ABSTRACT
The posttranslational methylation of the α-N-terminal amino group of proteins was first documented over 40 years ago, but the functional significance of this modification has been underexplored relative to lysine and arginine methylation. Increasing reports implicates α-N-terminal methylation as a widespread and critical regulator of mitosis, chromatin interactions, DNA repair, and translation fidelity. Here, we summarize advances in the current understanding of protein α-N-terminal methylation biological functions and mechanisms across eukaryotic organisms. Also, we describe the recent literature on substrate recognition and the discovery of potent and selective inhibitors for protein N-terminal methyltransferases. Finally, we summarize the emergent crosstalk between α-N-terminal methylation and other N-terminal modifications.
Subject(s)
Peptidomimetics/chemistry , Proteins/chemistry , Amines/chemistry , Arginine/chemistry , Chromatin/chemistry , DNA/chemistry , DNA Repair , Humans , Lysine/chemistry , Methylation , Methyltransferases/metabolism , Protein Binding , Protein Processing, Post-Translational , Signal Transduction , Substrate SpecificityABSTRACT
Protein arginine methyltransferase (PRMT) enzymes play a crucial role in RNA splicing, DNA damage repair, cell signaling, and differentiation. Arginine methylation is a prominent posttransitional modification of histones and various non-histone proteins that can either activate or repress gene expression. The aberrant expression of PRMTs has been linked to multiple abnormalities, notably cancer. Herein, we review a number of non-histone protein substrates for all nine members of human PRMTs and how PRMT-mediated non-histone arginine methylation modulates various diseases. Additionally, we highlight the most recent clinical studies for several PRMT inhibitors.
Subject(s)
Arginine/metabolism , Cardiovascular Diseases/enzymology , Metabolic Diseases/enzymology , Neoplasms/enzymology , Protein Processing, Post-Translational , Protein-Arginine N-Methyltransferases/metabolism , Transcription Factors/metabolism , Antineoplastic Agents/therapeutic use , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Enzyme Inhibitors/therapeutic use , Epigenesis, Genetic , Histones/genetics , Histones/metabolism , Humans , Metabolic Diseases/genetics , Metabolic Diseases/pathology , Methylation , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Protein-Arginine N-Methyltransferases/classification , Protein-Arginine N-Methyltransferases/genetics , RNA Splicing , Signal Transduction , Transcription Factors/antagonists & inhibitors , Transcription Factors/classification , Transcription Factors/geneticsABSTRACT
Nicotinamide N-methyltransferase (NNMT) catalyzes the methyl transfer from the cofactor S-adenosylmethionine to nicotinamide and other pyridine-containing compounds. NNMT is an important regulator for nicotinamide metabolism and methylation potential. Aberrant expression levels of NNMT have been implicated in cancer, metabolic, and neurodegenerative diseases, which makes NNMT a potential therapeutic target. Therefore, potent and selective NNMT inhibitors can serve as valuable tools to investigate the roles of NNMT in its mediated diseases. Here, we applied a rational strategy to design and synthesize the tight-binding bisubstrate inhibitor LL320 through a novel propargyl linker. LL320 demonstrates a Ki value of 1.6 ± 0.3 nM, which is the most potent inhibitor to date. The cocrystal structure of LL320 confirms its interaction with both the substrate and cofactor binding sites on NNMT. Importantly, this is the first example of using the propargyl linker to construct potent methyltransferase inhibitors, which will expand our understanding of the transition state of methyl transfer.
