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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\u2010\u00e0\u2010vis the heavier donor and acceptor counterparts, that is, low\u2010barrier, single\u2010well 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\u2010fold increase in catalytic turnover. A low\u2010barrier 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.<\/jats:p>","DOI":"10.1002\/anie.201908535","type":"journal-article","created":{"date-parts":[[2019,9,13]],"date-time":"2019-09-13T04:16:30Z","timestamp":1568348190000},"page":"16260-16266","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Low\u2010Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad"],"prefix":"10.1002","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7974-9238","authenticated-orcid":false,"given":"Prashasti","family":"Kumar","sequence":"first","affiliation":[{"name":"Graduate School of Genome Science and Technology University of Tennessee  Knoxville TN 37996 USA"},{"name":"Present address: Department of Pharmacological Sciences Icahn School of Medicine at Mount Sinai  New York NY 10029 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratul K.","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cellular and Molecular Biology University of Tennessee  Knoxville TN 37996 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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