Nigel Richards

Foundation for Applied Molecular Evolution, Alachua, Fl 32615, USA

Quantum Chemical Insights into Arginine Sidechain Modification

Sam Hay^1,2, Fabio Falcioni^1,2, Matt Cliff^1,2, Robert W. Molt, Jr.², G. Michael Blackburn⁴, and Nigel G. J. Richards⁵

¹Department of Chemistry, University of Manchester, Manchester, M13 9PL, UK; ²Manchester Institute of Biotechnology, University of Manchester, Manchester, M1 7DN, UK; ³Foundation ENSCO, Inc., Melbourne, FL 32940, USA; ⁴School of Biosciences, University of Sheffield, Sheffield, S10 2TN, UK; ⁵Foundation for Applied Molecular Evolution, Alachua, Fl 32615, USA

Abstract

A variety of important biological processes are underpinned by the enzyme-catalyzed modification of arginine side chains, including the regulation of gene expression, subversion of the immune system by bacterial pathogens, and a method of buffering ATP concentration in cells. This lecture will briefly outline recent insights, obtained by DFT analyses of quantum chemical cluster models for arginine kinase1 and the three families of protein arginine methyltransferase (PRMT), into how arginine side chains are activated for reaction. Our findings, when taken together with recent work by Rovira and co-workers on arginine N-glycosylation,2 suggest that arginine-modifying enzymes employ similar strategies for activating the cationic guanidinium moiety despite being evolutionarily unrelated.

References

[1] Falcioni, F. et al. ACS Catal. 2024, 14, 6650-6658. DOI: 10.1021/acscatal.4c00380

[2] Piniello, B. et al. ACS Catal. 2026, 16. Accepted. DOI: 10.1021/acscatal.5c07775