Substrate specificity, processivity, and kinetic mechanism of protein arginine methyltransferase 5.

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Amino Acid Sequence; Animals; Arginine; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Catalysis; Kinetics; Methylation; Molecular Sequence Data; Protein-Arginine N-Methyltransferases; Substrate Specificity


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


Protein arginine methyltransferases (PRMTs) have emerged as attractive therapeutic targets for heart disease and cancers. PRMT5 is a particularly interesting target because it is overexpressed in blood, breast, colon, and stomach cancers and promotes cell survival in the face of DNA damaging agents. As the only known member of the PRMT enzyme family to catalyze the formation of mono- and symmetrically dimethylated arginine residues, PRMT5 is also mechanistically unique. As a part of a program to characterize the mechanisms and regulation of the PRMTs and develop chemical probes targeting these enzymes, we characterized the substrate specificity, processivity, and kinetic mechanism of bacterially expressed Caenorhabditis elegans PRMT5 (cPRMT5). In this report, we demonstrate that distal positively charged residues contribute to substrate binding in a synergistic fashion. Additionally, we show that cPRMT5 catalyzes symmetric dimethylation in a distributive fashion. Finally, the results of initial velocity, product, and dead-end inhibition studies indicate that cPRMT5 uses a rapid equilibrium random mechanism with dead-end EAP and EBQ complexes. In total, these studies will guide PRMT5 inhibitor development and lay the foundation for studying how the activity of this medically relevant enzyme is regulated.

DOI of Published Version



Biochemistry. 2013 Aug 13;52(32):5430-40. doi: 10.1021/bi4005123. Epub 2013 Aug 1. Link to article on publisher's site

Journal/Book/Conference Title



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

Related Resources

Link to Article in PubMed