Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad

Kumar, Prashasti; Agarwal, Pratul K.; Waddell, M. Brett; Mittag, Tanja; Serpersu, Engin H.; Cuneo, Matthew J.

doi:10.1002/anie.201908535

Title: Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad

Journal Article · 24 September 2019 · Angewandte Chemie (International Edition)

DOI: https://doi.org/10.1002/anie.201908535 · OSTI ID:1566162

^[1]; Agarwal, Pratul K. ^[2]; Waddell, M. Brett ^[3]; Mittag, Tanja ^[4];

^[5];

^[6]

Graduate School of Genome Science and Technology University of Tennessee Knoxville TN 37996 USA, Present address: Department of Pharmacological Sciences Icahn School of Medicine at Mount Sinai New York NY 10029 USA
Department of Biochemistry and Cellular and Molecular Biology University of Tennessee Knoxville TN 37996 USA
Molecular Interaction Analysis Shared Resource St. Jude Children's Research Hospital Memphis TN 38105 USA
Department of Structural Biology St. Jude Children's Research Hospital Memphis TN 38105 USA
Department of Biochemistry and Cellular and Molecular Biology University of Tennessee Knoxville TN 37996 USA, National Science Foundation Alexandria VA 22314 USA
Department of Structural Biology St. Jude Children's Research Hospital Memphis TN 38105 USA, Oak Ridge National Laboratory Oak Ridge TN 37830 USA

Abstract The position, bonding and dynamics of hydrogen atoms in the catalytic centers of proteins are essential for catalysis. The role of short hydrogen bonds in catalysis has remained highly debated and led to establishment of several distinctive geometrical arrangements of hydrogen atoms vis‐à‐vis the heavier donor and acceptor counterparts, that is, low‐barrier, single‐well or short canonical hydrogen bonds. Here we demonstrate how the position of a hydrogen atom in the catalytic triad of an aminoglycoside inactivating enzyme leads to a thirty‐fold increase in catalytic turnover. A low‐barrier hydrogen bond is present in the enzyme active site for the substrates that are turned over the best, whereas a canonical hydrogen bond is found with the least preferred substrate. This is the first comparison of these hydrogen bonds involving an identical catalytic network, while directly demonstrating how active site electrostatics adapt to the electronic nature of substrates to tune catalysis.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: FWP ERKP291

OSTI ID:: 1566162

Journal Information:: Angewandte Chemie (International Edition), Journal Name: Angewandte Chemie (International Edition) Vol. 58 Journal Issue: 45; ISSN 1433-7851

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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Cited by: 16 works

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