Activity-based protein profiling of protein arginine methyltransferase 1
Department of Biochemistry and Molecular Pharmacology
Breast Neoplasms; Cell Line, Tumor; *Drug Design; Enzyme Inhibitors; Female; Humans; Inhibitory Concentration 50; Protein-Arginine N-Methyltransferases; Repressor Proteins
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
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 approximately 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.
DOI of Published Version
ACS Chem Biol. 2011 Oct 21;6(10):1127-35. doi: 10.1021/cb2001473. Epub 2011 Aug 23. Link to article on publisher's site
ACS chemical biology
Obianyo, Obiamaka; Causey, Corey P.; Jones, Justin E.; and Thompson, Paul R., "Activity-based protein profiling of protein arginine methyltransferase 1" (2011). Thompson Lab Publications. 43.