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QM/MM Studies of Dph5-A Promiscuous Methyltransferase in the Eukaryotic Biosynthetic Pathway of Diphthamide

Journal article
Authors Johanna Hörberg
P. Saenz-Mendez
Leif A Eriksson
Published in Journal of Chemical Information and Modeling
Volume 58
Issue 7
Pages 1406-1414
ISSN 1549-9596
Publication year 2018
Published at Department of Chemistry and Molecular Biology
Pages 1406-1414
Language en
Keywords mechanism, step, efficient, Pharmacology & Pharmacy, Chemistry, Computer Science
Subject categories Cell and molecular biology, Chemical Sciences


Eukaryotic diphthine synthase, Dph5, is a promiscuous methyltransferase that catalyzes an extraordinary N,O-tetramethylation of 2-(3-carboxy-3-aminopropyl)-L-histidine (ACP) to yield diphthine methyl ester (DTM). These are intermediates in the biosynthesis of the post-translation ally modified histidine residue diphthamide (DTA), a unique and essential residue part of the eukaryotic elongation factor 2 (eEF2). Herein, the promiscuity of Saccharomyces cerevisiae Dph5 has been studied with in silico approaches, including homology modeling to provide the structure of Dph5, protein protein docking and molecular dynamics to construct the Dph5-eEF2 complex, and quantum mechanics/molecular mechanics (QM/MM) calculations to outline a plausible mechanism. The calculations show that the methylation of ACP follows a typical S(N)2 mechanism, initiating with a complete methylation (trimethylation) at the N-position, followed by the single O-methylation. For each of the three N-methylation reactions, our calculations support a stepwise mechanism, which first involve proton transfer through a bridging water to a conserved aspartate residue D165, followed by a methyl transfer. Once fully methylated, the trimethyl amino group forms a weak electrostatic interaction with D165, which allows the carboxylate group of diphthine to attain the right orientation for the final methylation step to be accomplished.

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