Title
Kinetic mechanism of protein arginine methyltransferase 1
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology
Publication Date
2008-09-30
Document Type
Article
Subjects
Catalysis; Heart Diseases; Humans; Isoenzymes; Kinetics; Methylation; Peptide Fragments; Protein-Arginine N-Methyltransferases; purification
Disciplines
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
Abstract
Protein arginine methyltransferases (PRMTs) are SAM-dependent enzymes that catalyze the mono- and dimethylation of peptidyl arginine residues. Although all PRMTs produce monomethyl arginine (MMA), type 1 PRMTs go on to form asymmetrically dimethylated arginine (ADMA), while type 2 enzymes form symmetrically dimethylated arginine (SDMA). PRMT1 is the major type 1 PRMT in vivo, thus it is the primary producer of the competitive NOS inhibitor, ADMA. Hence, potent inhibitors, which are highly selective for this particular isozyme, could serve as excellent therapeutics for heart disease. However, the design of such inhibitors is impeded by a lack of information regarding this enzyme's kinetic and catalytic mechanisms. Herein we report an analysis of the kinetic mechanism of human PRMT1 using both an unmethylated and a monomethylated substrate peptide based on the N-terminus of histone H4. The results of initial velocity and product and dead-end inhibition experiments indicate that PRMT1 utilizes a rapid equilibrium random mechanism with the formation of dead-end EAP and EBQ complexes. This mechanism is gratifyingly consistent with previous results demonstrating that PRMT1 catalyzes substrate dimethylation in a partially processive manner.
DOI of Published Version
10.1021/bi800904m
Source
Biochemistry. 2008 Sep 30;47(39):10420-7. doi: 10.1021/bi800904m. Link to article on publisher's site. Epub 2008 Sep 5.
Journal/Book/Conference Title
Biochemistry
Related Resources
Repository Citation
Obianyo, Obiamaka; Osborne, Tanesha C.; and Thompson, Paul R., "Kinetic mechanism of protein arginine methyltransferase 1" (2008). Thompson Lab Publications. 65.
https://escholarship.umassmed.edu/thompson/65
Comments
At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.