Protein Arginine N-Methyltransferase Substrate Preferences for Different Nη-Substituted Arginyl Peptides

• Published in: Chembiochem : a European journal of chemical biology 2014-07, Vol.15 (11), p.1607-1613
• Main Authors: Thomas, Dylan, Koopmans, Timo, Lakowski, Ted M., Kreinin, Helmi, Vhuiyan, Mynol I., Sedlock, Shona A., Bui, Jennifer M., Martin, Nathaniel I., Frankel, Adam
• Format: Article
• Language: English
• Subjects: Arginine - metabolism; arginine analogues; enzymes; methylation; Molecular Structure; peptides; Peptides - chemistry; Peptides - metabolism; protein arginine N-methyltransferases; Protein-Arginine N-Methyltransferases - chemistry; Protein-Arginine N-Methyltransferases - metabolism; Substrate Specificity
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201402045

Protein arginine N‐methyltransferases (PRMTs) catalyze methyl‐group transfer from S‐adenosyl‐L‐methionine onto arginine residues in proteins. In this study, modifications were introduced at the guanidine moiety of a peptidyl arginine residue to investigate how changes to the PRMT substrate can modulate enzyme activity. We found that peptides bearing Nη‐hydroxy or Nη‐amino substituted arginine showed higher apparent kcat values than for the monomethylated substrate when using PRMT1, whereas this catalytic preference was not observed for PRMT4 and PRMT6. Methylation by compromised PRMT1 variants E153Q and D51N further supports the finding that the N‐hydroxy substitution facilitates methyl transfer by tuning the reactivity of the guanidine moiety. In contrast, Nη‐nitro and Nη‐canavanine substituted substrates inhibit PRMT activity. These findings demonstrate that methylation of these PRMT substrates is dependent on the nature of the modification at the guanidine moiety. A little goes a long way: Various heteroatom substituents at the guanidine moiety of an arginine residue in an established substrate peptide can alter the protein arginine N‐methyltransferase (PRMT) activity toward it. Depending on the electrostatic nature of the substituent incorporated, PRMT activity toward the substrate peptide can be diminished, abolished, or, surprisingly, enhanced.