Substrate specificity, processivity, and kinetic mechanism of protein arginine methyltransferase 5.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2013-08-13Keywords
Amino Acid SequenceAnimals
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
Metadata
Show full item recordAbstract
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.Source
Biochemistry. 2013 Aug 13;52(32):5430-40. doi: 10.1021/bi4005123. Epub 2013 Aug 1. Link to article on publisher's siteDOI
10.1021/bi4005123Permanent Link to this Item
http://hdl.handle.net/20.500.14038/50013Notes
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1021/bi4005123