title: In situ generation of a bisubstrate analogue for protein arginine methyltransferase 1.
abstract: Protein arginine methyltransferases (PRMTs) are (S)-adenosylmethionine (SAM)-dependent methyltransferases that catalyze the post-translational methylation of Arg residues in a variety of different proteins involved in transcriptional regulation and RNA splicing (e.g., histones H2A, H3, and H4). Herein, we describe the use of an N-mustard, 5'-(diaminobutyric acid)-N-iodoethyl-5'-deoxyadenosine ammonium hydrochloride (AAI), to generate a bisubstrate analogue inhibitor of PRMT1. Using the approach outlined in this communication, it should be possible to generate bisubstrate analogue-based inhibitors of PRMT isozymes that are potent and highly selective for a particular isozyme. The fact that PRMT1 catalyzes AAI transfer is also significant because with appropriate modifications (e.g., functionalization with pendant azido or alkyne functionalities) this compound could be used for proteomic applications to identify novel PRMT substrates.
authors.affiliation: Department of Chemistry & Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208, USA.
authors.forename: Tanesha
authors.initials: T
authors.lastname: Osborne
authors.forename: Rachel L Weller
authors.initials: RL
authors.lastname: Roska
authors.forename: Scott R
authors.initials: SR
authors.lastname: Rajski
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
mesh_terms: D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes; D007700:Kinetics; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010455:Peptides; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases