title: Activity-based protein profiling of protein arginine methyltransferase 1.
abstract: The protein arginine methyltransferases (PRMTs) are SAM-dependent enzymes that catalyze the mono- and dimethylation of peptidyl arginine residues. PRMT1 is the founding member of the PRMT family, and this isozyme is responsible for methylating ∼85% of the arginine residues in mammalian cells. Additionally, PRMT1 activity is aberrantly upregulated in heart disease and cancer. As a part of a program to develop isozyme-specific PRMT inhibitors, we recently described the design and synthesis of C21, a chloroacetamidine bearing histone H4 tail analogue that acts as an irreversible PRMT1 inhibitor. Given the covalent nature of the interaction, we set out to develop activity-based probes (ABPs) that could be used to characterize the physiological roles of PRMT1. Herein, we report the design, synthesis, and characterization of fluorescein-conjugated C21 (F-C21) and biotin-conjugated C21 (B-C21) as PRMT1-specific ABPs. Additionally, we provide the first evidence that PRMT1 activity is negatively regulated in a spatial and temporal fashion.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, Florida 33458, United States.
authors.forename: Obiamaka
authors.initials: O
authors.lastname: Obianyo
authors.forename: Corey P
authors.initials: CP
authors.lastname: Causey
authors.forename: Justin E
authors.initials: JE
authors.lastname: Jones
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases