Title

Protein arginine methyltransferase 1: positively charged residues in substrate peptides distal to the site of methylation are important for substrate binding and catalysis

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

11-20-2007

Document Type

Article

Medical Subject Headings

Amino Acid Sequence; Animals; Binding Sites; Catalysis; Enzyme Inhibitors; Histones; Humans; Kinetics; Mass Spectrometry; Methylation; Models, Molecular; Molecular Sequence Data; Peptides; Protein-Arginine N-Methyltransferases; inhibitors; Rats; Recombinant Proteins; Repressor Proteins; Substrate Specificity

Disciplines

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

Abstract

Protein arginine methyltransferases (PRMTs) are a group of eukaryotic enzymes that catalyze the methylation of Arg residues in a variety of proteins (e.g., histones H3 and H4), and their activities influence a wide range of cellular processes, including cell growth, RNA splicing, differentiation, and transcriptional regulation. Dysregulation of these enzymes has been linked to heart disease and cancer, suggesting this enzyme family as a novel therapeutic target. To aid the development of PRMT inhibitors, we characterized the substrate specificity of both the rat and human PRMT1 orthologues using histone based peptide substrates. N- and C-terminal truncations to identify a minimal peptide substrate indicate that long-range interactions between enzyme and substrate are important for high rates of substrate capture. The importance of these long-range interactions to substrate capture were confirmed by "mutagenesis" experiments on a minimal peptide substrate. Inhibition studies on S-adenosyl-homocysteine, thioadenosine, methylthioadenosine, homocysteine, and sinefungin suggest that potent and selective bisubstrate analogue inhibitor(s) for PRMT1 can be developed by linking a histone based peptide substrate to homocysteine or sinefungin. Additionally, we present evidence that PRMT1 utilizes a partially processive mechanism to dimethylate its substrates.

Rights and Permissions

Citation: Biochemistry. 2007 Nov 20;46(46):13370-81. Link to article on publisher's site. Epub 2007 Oct 26.

Comments

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

Related Resources

Link to Article in PubMed