Encoding of Promiscuity in an Aminoglycoside Acetyltransferase

Kumar, Prashasti; Selvaraj, Brinda; Serpersu, Engin H.; Cuneo, Matthew J.

doi:10.1021/acs.jmedchem.8b01393

Title: Encoding of Promiscuity in an Aminoglycoside Acetyltransferase

Journal Article · 21 October 2018 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.8b01393 · OSTI ID:1484803

Kumar, Prashasti ^[1]; Selvaraj, Brinda ^[2];

^[3];

^[4]

Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Neutron Sciences Directorate
Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); National Science Foundation (NSF), Alexandria, VA (United States)
St. Jude Children’s Research Hospital, Memphis, TN (United States)

Aminoglycoside antibiotics are a large family of antibiotics that can be divided into two distinct classes on the basis of the substitution pattern of the central deoxystreptamine ring. Although aminoglycosides are chemically, structurally, and topologically diverse, some aminoglycoside-modifying enzymes (AGMEs) are able to inactivate as many as 15 aminoglycosides from the two main classes, the kanamycin- and neomycin-based antibiotics. In this paper, we present the crystal structure of a promiscuous AGME, aminoglycoside-N3-acetyltransferase-IIIb (AAC-IIIb), in the apo form, in binary drug (sisomicin, neomycin, and paromomycin) and coenzyme A (CoASH) complexes, and in the ternary neomycin–CoASH complex. These data provide a structural framework for interpretation of the thermodynamics of enzyme–ligand interactions and the role of solvent in the recognition of ligands. In combination with the recent structure of an AGME that does not have broad substrate specificity, these structures allow for the direct determination of how antibiotic promiscuity is encoded in some AGMEs.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); National Science Foundation (NSF); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1484803

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 22 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad Kumar, Prashasti; Agarwal, Pratul K.; Waddell, M. Brett Angewandte Chemie, Vol. 131, Issue 45 https://doi.org/10.1002/ange.201908535	journal	September 2019
Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad Kumar, Prashasti; Agarwal, Pratul K.; Waddell, M. Brett Angewandte Chemie International Edition, Vol. 58, Issue 45 https://doi.org/10.1002/anie.201908535	journal	November 2019

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