title: Small molecule regulators of protein arginine methyltransferases.
abstract: Here we report the identification of small molecules that specifically inhibit protein arginine N-methyltransferase (PRMT) activity. PRMTs are a family of proteins that either monomethylate or dimethylate the guanidino nitrogen atoms of arginine side chains. This common post-translational modification is implicated in protein trafficking, signal transduction, and transcriptional regulation. Most methyltransferases use the methyl donor, S-adenosyl-L-methionine (AdoMet), as a cofactor. Current methyltransferase inhibitors display limited specificity, indiscriminately targeting all enzymes that use AdoMet. In this screen we have identified a primary compound, AMI-1, that specifically inhibits arginine, but not lysine, methyltransferase activity in vitro and does not compete for the AdoMet binding site. Furthermore, AMI-1 prevents in vivo arginine methylation of cellular proteins and can modulate nuclear receptor-regulated transcription from estrogen and androgen response elements, thus operating as a brake on certain hormone actions.
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
authors.forename: Donghang
authors.initials: D
authors.lastname: Cheng
authors.forename: Neelu
authors.initials: N
authors.lastname: Yadav
authors.forename: Randall W
authors.initials: RW
authors.lastname: King
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Weinstein
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
mesh_terms: D001120:Arginine / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D020128:Inhibitory Concentration 50; D008027:Light; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012436:S-Adenosylmethionine / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D000939:Epitopes; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D012436:S-Adenosylmethionine; D001120:Arginine; D008156:Luciferases; D011484:Protein-Arginine N-Methyltransferases; D005982:Glutathione Transferase; D008239:Lysine; D009584:Nitrogen