Title

Activity-based protein profiling of protein arginine methyltransferase 1

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date

10-21-2011

Document Type

Article

Subjects

Breast Neoplasms; Cell Line, Tumor; *Drug Design; Enzyme Inhibitors; Female; Humans; Inhibitory Concentration 50; Protein-Arginine N-Methyltransferases; Repressor Proteins

Disciplines

Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics

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 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

10.1021/cb2001473

Source

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

Journal/Book/Conference Title

ACS chemical biology

Comments

At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.

Related Resources

Link to Article in PubMed

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