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

Authors

  • Dylan Thomas,

    1. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3 (Canada)
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    • These authors contributed equally to this work.

  • Timo Koopmans,

    1. Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht (The Netherlands)
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    • These authors contributed equally to this work.

  • Dr. Ted M. Lakowski,

    1. Faculty of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba, R3E 0T5 (Canada)
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  • Helmi Kreinin,

    1. Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht (The Netherlands)
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  • Mynol I. Vhuiyan,

    1. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3 (Canada)
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  • Shona A. Sedlock,

    1. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3 (Canada)
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  • Dr. Jennifer M. Bui,

    1. Jacobs School of Engineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0436 (USA)
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  • Dr. Nathaniel I. Martin,

    Corresponding author
    1. Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht (The Netherlands)
    • Nathaniel I. Martin, Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht (The Netherlands)===

      Adam Frankel, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3 (Canada)===

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  • Dr. Adam Frankel

    Corresponding author
    1. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3 (Canada)
    • Nathaniel I. Martin, Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht (The Netherlands)===

      Adam Frankel, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia V6T 1Z3 (Canada)===

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Abstract

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.

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