A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad
Abstract
One group of enzymes that confer resistance to aminoglycoside antibiotics through covalent modification belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily. We show how a unique GNAT subfamily member uses a previously unidentified noncanonical catalytic triad, consisting of a glutamic acid, a histidine, and the antibiotic substrate itself, which acts as a nucleophile and attacks the acetyl donor molecule. Neutron diffraction studies allow for unambiguous identification of a low-barrier hydrogen bond, predicted in canonical catalytic triads to increase basicity of the histidine. This work highlights the role of this unique catalytic triad in mediating antibiotic resistance while providing new insights into the design of the next generation of aminoglycosides.
- Authors:
-
[1];
[2];
[3]
- Univ. of Tennessee, Knoxville, TN (United States). Joint Inst. of Neutron Science. Graduate School of Genome Science and Technology
- Univ. of Tennessee, Knoxville, TN (United States). Joint Inst. of Neutron Science. Graduate School of Genome Science and Technology; National Science Foundation (NSF), Alexandria, VA (United States); Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Neutron Sciences Directorate
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1625990
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science Advances
- Additional Journal Information:
- Journal Volume: 4; Journal Issue: 4; Journal ID: ISSN 2375-2548
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; Science & Technology - Other Topics
Citation Formats
Kumar, Prashasti, Serpersu, Engin H., and Cuneo, Matthew J. A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad. United States: N. p., 2018.
Web. doi:10.1126/sciadv.aas8667.
Kumar, Prashasti, Serpersu, Engin H., & Cuneo, Matthew J. A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad. United States. https://doi.org/10.1126/sciadv.aas8667
Kumar, Prashasti, Serpersu, Engin H., and Cuneo, Matthew J. Sun .
"A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad". United States. https://doi.org/10.1126/sciadv.aas8667. https://www.osti.gov/servlets/purl/1625990.
@article{osti_1625990,
title = {A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad},
author = {Kumar, Prashasti and Serpersu, Engin H. and Cuneo, Matthew J.},
abstractNote = {One group of enzymes that confer resistance to aminoglycoside antibiotics through covalent modification belongs to the GCN5-related N-acetyltransferase (GNAT) superfamily. We show how a unique GNAT subfamily member uses a previously unidentified noncanonical catalytic triad, consisting of a glutamic acid, a histidine, and the antibiotic substrate itself, which acts as a nucleophile and attacks the acetyl donor molecule. Neutron diffraction studies allow for unambiguous identification of a low-barrier hydrogen bond, predicted in canonical catalytic triads to increase basicity of the histidine. This work highlights the role of this unique catalytic triad in mediating antibiotic resistance while providing new insights into the design of the next generation of aminoglycosides.},
doi = {10.1126/sciadv.aas8667},
journal = {Science Advances},
number = 4,
volume = 4,
place = {United States},
year = {Sun Apr 01 00:00:00 EDT 2018},
month = {Sun Apr 01 00:00:00 EDT 2018}
}
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Fig. 1: Binary complexes of AAC-VIa. (A) Surface representation of AAC-VIa–sisomicin (green carbon atoms) binary complex superimposed on the enzyme–acetyl-CoA (yellow carbon atoms) binary complex. The AAC-VIa surface cavities that bind sisomicin and coenzyme A (CoASH) are colored black and gray, respectively, whereas the catalytic triad is shown inmagenta. (B)more »
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Works referenced in this record:
Phaser.MRage: automated molecular replacement.
text, January 2013
- Bunkóczi, Gábor; Echols, Nathaniel; McCoy, Airlie
- Apollo - University of Cambridge Repository
Mantid—Data analysis and visualization package for neutron scattering and SR experiments
journal, November 2014
- Arnold, O.; Bilheux, J. C.; Borreguero, J. M.
- Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, Vol. 764
Is Aspartate 52 Essential for Catalysis by Chicken Egg White Lysozyme? The Role of Natural Substrate-Assisted Hydrolysis †
journal, January 1996
- Matsumura, Ichiro; Kirsch, Jack F.
- Biochemistry, Vol. 35, Issue 6
Trypsin specificity increased through substrate-assisted catalysis
journal, September 1995
- Corey, D. R.; Willett, W. S.; Coombs, G. S.
- Biochemistry, Vol. 34, Issue 36
The Most Frequent Aminoglycoside Resistance Mechanisms--Changes with Time and Geographic Area: A Reflection of Aminoglycoside Usage Patterns?
journal, January 1997
- Miller, G. H.; Sabatelli, F. J.; Hare, R. S.
- Clinical Infectious Diseases, Vol. 24, Issue Supplement 1
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020
- Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe
- JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6
Towards automated crystallographic structure refinement with phenix.refine
journal, March 2012
- Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel
- Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4
Metal ion-mediated substrate-assisted catalysis in type II restriction endonucleases
journal, November 1998
- Horton, N. C.; Newberry, K. J.; Perona, J. J.
- Proceedings of the National Academy of Sciences, Vol. 95, Issue 23
Interaction of antibiotics with functional sites in 16S ribosomal RNA
journal, June 1987
- Moazed, Danesh; Noller, Harry F.
- Nature, Vol. 327, Issue 6121
Inactivation of antibiotics and the dissemination of resistance genes
journal, April 1994
- Davies, J.
- Science, Vol. 264, Issue 5157
Direct determination of the protonation states of aspartic acid-102 and histidine-57 in the tetrahedral intermediate of the serine proteases: neutron structure of trypsin
journal, October 1981
- Kossiakoff, Anthony A.; Spencer, Steven A.
- Biochemistry, Vol. 20, Issue 22
Thermodynamics of an aminoglycoside modifying enzyme with low substrate promiscuity: The aminoglycoside N3 acetyltransferase-VIa : Thermodynamic Basis of Ligand Promiscuity
journal, March 2017
- Kumar, Prashasti; Serpersu, Engin H.
- Proteins: Structure, Function, and Bioinformatics, Vol. 85, Issue 7
Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases
journal, February 2003
- Powers, James C.; Asgian, Juliana L.; Ekici, Oezlem Dogan
- ChemInform, Vol. 34, Issue 7
Engineering enzyme specificity by "substrate-assisted catalysis"
journal, July 1987
- Carter, P.; Wells, J.
- Science, Vol. 237, Issue 4813
Crystal structure of HIV-1 protease in situ product complex and observation of a low-barrier hydrogen bond between catalytic aspartates
journal, November 2006
- Das, A.; Prashar, V.; Mahale, S.
- Proceedings of the National Academy of Sciences, Vol. 103, Issue 49
LAUEGEN version 6.0 and INTLDM
journal, June 1998
- Campbell, J. W.; Hao, Q.; Harding, M. M.
- Journal of Applied Crystallography, Vol. 31, Issue 3
Crystal Structure of a GCN5-Related N-acetyltransferase
journal, August 1998
- Wolf, Eva; Vassilev, Alex; Makino, Yasutaka
- Cell, Vol. 94, Issue 4
GCN5-Related N-Acetyltransferases: A Structural Overview
journal, June 2000
- Dyda, Fred; Klein, David C.; Hickman, Alison Burgess
- Annual Review of Biophysics and Biomolecular Structure, Vol. 29, Issue 1
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019
- Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman
- Nature Communications, Vol. 10, Issue 1
Substrate-assisted catalysis: Molecular basis and biological significance
journal, January 2000
- Dall'Acqua, William; Carter, Paul
- Protein Science, Vol. 9, Issue 1
Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes.
journal, January 1993
- Shaw, K. J.; Rather, P. N.; Hare, R. S.
- Microbiological Reviews, Vol. 57, Issue 1
An explanation for rapid enzyme-catalyzed proton abstraction from carbon acids: importance of late transition states in concerted mechanisms
journal, December 1993
- Gerlt, John A.; Gassman, Paul G.
- Journal of the American Chemical Society, Vol. 115, Issue 24
Correction to Thermodynamics and Kinetics of Association of Antibiotics with the Aminoglycoside Acetyltransferase (3)-IIIb, a Resistance-Causing Enzyme
journal, October 2013
- Norris, Adrianne L.; Özen, Can; Serpersu, Engin H.
- Biochemistry, Vol. 52, Issue 43
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
The Macromolecular Neutron Diffractometer MaNDi at the Spallation Neutron Source
journal, July 2015
- Coates, Leighton; Cuneo, Matthew J.; Frost, Matthew J.
- Journal of Applied Crystallography, Vol. 48, Issue 4
A New Concept for the Mechanism of Action of Chymotrypsin: The Role of the Low-Barrier Hydrogen Bond †
journal, April 1997
- Cassidy, Constance S.; Lin, Jing; Frey, Perry A.
- Biochemistry, Vol. 36, Issue 15
Mechanistic and Structural Analysis of Aminoglycoside N -Acetyltransferase AAC(6′)-Ib and Its Bifunctional, Fluoroquinolone-Active AAC(6′)-Ib-cr Variant † ‡
journal, September 2008
- Vetting, Matthew W.; Park, Chi Hye; Hegde, Subray S.
- Biochemistry, Vol. 47, Issue 37
Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography
journal, March 2009
- Adachi, M.; Ohhara, T.; Kurihara, K.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 12
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases
journal, December 2002
- Powers, James C.; Asgian, Juliana L.; Ekici, Özlem Doǧan
- Chemical Reviews, Vol. 102, Issue 12
A low-barrier hydrogen bond in the catalytic triad of serine proteases
journal, June 1994
- Frey, P.; Whitt, S.; Tobin, J.
- Science, Vol. 264, Issue 5167
The Low Barrier Hydrogen Bond in Enzymatic Catalysis
journal, October 1998
- Cleland, W. Wallace; Frey, Perry A.; Gerlt, John A.
- Journal of Biological Chemistry, Vol. 273, Issue 40
Interactions of Coenzyme A with the Aminoglycoside Acetyltransferase (3)-IIIb and Thermodynamics of a Ternary System
journal, May 2010
- Norris, Adrianne L.; Serpersu, Engin H.
- Biochemistry, Vol. 49, Issue 19
Why have mutagenesis studies not located the general base in ras p21
journal, July 1994
- Schweins, T.; Langen, R.; Warshel, A.
- Nature Structural & Molecular Biology, Vol. 1, Issue 7
Ligand promiscuity through the eyes of the aminoglycoside N 3 acetyltransferase IIa : Molecular Basis of Ligand Promiscuity
journal, June 2013
- Norris, Adrianne L.; Serpersu, Engin H.
- Protein Science, Vol. 22, Issue 7
Structural Analysis of a Putative Aminoglycoside N-Acetyltransferase from Bacillus anthracis
journal, July 2011
- Klimecka, Maria M.; Chruszcz, Maksymilian; Font, Jose
- Journal of Molecular Biology, Vol. 410, Issue 3
Thermodynamics and Kinetics of Association of Antibiotics with the Aminoglycoside Acetyltransferase (3)-IIIb, a Resistance-Causing Enzyme
journal, May 2010
- Norris, Adrianne L.; Özen, Can; Serpersu, Engin H.
- Biochemistry, Vol. 49, Issue 19
Combined High-Resolution Neutron and X-ray Analysis of Inhibited Elastase Confirms the Active-Site Oxyanion Hole but Rules against a Low-Barrier Hydrogen Bond
journal, August 2009
- Tamada, Taro; Kinoshita, Takayoshi; Kurihara, Kazuo
- Journal of the American Chemical Society, Vol. 131, Issue 31
Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes
journal, March 1993
- Shaw, K. J.; Rather, P. N.; Hare, R. S.
- Microbiological Reviews, Vol. 57, Issue 1
The Protein Data Bank
journal, May 2002
- Berman, Helen M.; Battistuz, Tammy; Bhat, T. N.
- Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 6
Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases
journal, February 2003
- Powers, James C.; Asgian, Juliana L.; Ekici, Oezlem Dogan
- ChemInform, Vol. 34, Issue 7
Structural Analysis of a Putative Aminoglycoside N-Acetyltransferase from Bacillus anthracis
journal, July 2011
- Klimecka, Maria M.; Chruszcz, Maksymilian; Font, Jose
- Journal of Molecular Biology, Vol. 410, Issue 3
Crystal structure of an aminoglycoside 6′-N-acetyltransferase: defining the GCN5-related N-acetyltransferase superfamily fold
journal, May 1999
- Wybenga-Groot, Leanne E.; Draker, Kari-ann; Wright, Gerard D.
- Structure, Vol. 7, Issue 5
Trypsin specificity increased through substrate-assisted catalysis
journal, September 1995
- Corey, D. R.; Willett, W. S.; Coombs, G. S.
- Biochemistry, Vol. 34, Issue 36
Direct determination of the protonation states of aspartic acid-102 and histidine-57 in the tetrahedral intermediate of the serine proteases: neutron structure of trypsin
journal, October 1981
- Kossiakoff, Anthony A.; Spencer, Steven A.
- Biochemistry, Vol. 20, Issue 22
Thermodynamics and Kinetics of Association of Antibiotics with the Aminoglycoside Acetyltransferase (3)-IIIb, a Resistance-Causing Enzyme
journal, May 2010
- Norris, Adrianne L.; Özen, Can; Serpersu, Engin H.
- Biochemistry, Vol. 49, Issue 19
Interactions of Coenzyme A with the Aminoglycoside Acetyltransferase (3)-IIIb and Thermodynamics of a Ternary System
journal, May 2010
- Norris, Adrianne L.; Serpersu, Engin H.
- Biochemistry, Vol. 49, Issue 19
Mechanistic and Structural Analysis of Aminoglycoside N -Acetyltransferase AAC(6′)-Ib and Its Bifunctional, Fluoroquinolone-Active AAC(6′)-Ib-cr Variant † ‡
journal, September 2008
- Vetting, Matthew W.; Park, Chi Hye; Hegde, Subray S.
- Biochemistry, Vol. 47, Issue 37
Is Aspartate 52 Essential for Catalysis by Chicken Egg White Lysozyme? The Role of Natural Substrate-Assisted Hydrolysis †
journal, January 1996
- Matsumura, Ichiro; Kirsch, Jack F.
- Biochemistry, Vol. 35, Issue 6
A New Concept for the Mechanism of Action of Chymotrypsin: The Role of the Low-Barrier Hydrogen Bond †
journal, April 1997
- Cassidy, Constance S.; Lin, Jing; Frey, Perry A.
- Biochemistry, Vol. 36, Issue 15
An explanation for rapid enzyme-catalyzed proton abstraction from carbon acids: importance of late transition states in concerted mechanisms
journal, December 1993
- Gerlt, John A.; Gassman, Paul G.
- Journal of the American Chemical Society, Vol. 115, Issue 24
Interaction of antibiotics with functional sites in 16S ribosomal RNA
journal, June 1987
- Moazed, Danesh; Noller, Harry F.
- Nature, Vol. 327, Issue 6121
Why have mutagenesis studies not located the general base in ras p21
journal, July 1994
- Schweins, T.; Langen, R.; Warshel, A.
- Nature Structural & Molecular Biology, Vol. 1, Issue 7
Investigation of the catalytic triad of arylamine N-acetyltransferases: essential residues required for acetyl transfer to arylamines
journal, August 2005
- Sandy, James; Mushtaq, Adeel; Holton, Simon J.
- Biochemical Journal, Vol. 390, Issue 1
Crystal structure of HIV-1 protease in situ product complex and observation of a low-barrier hydrogen bond between catalytic aspartates
journal, November 2006
- Das, A.; Prashar, V.; Mahale, S.
- Proceedings of the National Academy of Sciences, Vol. 103, Issue 49
The Low Barrier Hydrogen Bond in Enzymatic Catalysis
journal, October 1998
- Cleland, W. Wallace; Frey, Perry A.; Gerlt, John A.
- Journal of Biological Chemistry, Vol. 273, Issue 40
New N -Acetyltransferase Fold in the Structure and Mechanism of the Phosphonate Biosynthetic Enzyme FrbF
journal, August 2011
- Bae, Brian; Cobb, Ryan E.; DeSieno, Matthew A.
- Journal of Biological Chemistry, Vol. 286, Issue 41
Phaser.MRage : automated molecular replacement
journal, October 2013
- Bunkóczi, Gábor; Echols, Nathaniel; McCoy, Airlie J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 11
Substrate-assisted catalysis: Molecular basis and biological significance
journal, January 2000
- Dall'Acqua, William; Carter, Paul
- Protein Science, Vol. 9, Issue 1
Analysis of the aac(3)-VIa gene encoding a novel 3-N-acetyltransferase.
journal, October 1993
- Rather, P. N.; Mann, P. A.; Mierzwa, R.
- Antimicrobial Agents and Chemotherapy, Vol. 37, Issue 10
Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes
journal, March 1993
- Shaw, K. J.; Rather, P. N.; Hare, R. S.
- Microbiological Reviews, Vol. 57, Issue 1
GCN5-Related N-Acetyltransferases: A Structural Overview
journal, June 2000
- Dyda, Fred; Klein, David C.; Hickman, Alison Burgess
- Annual Review of Biophysics and Biomolecular Structure, Vol. 29, Issue 1
Mantid - Data Analysis and Visualization Package for Neutron Scattering and $μSR$ Experiments
text, January 2014
- Arnold, O.; Bilheux, J. C.; Borreguero, J. M.
- arXiv
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- Kumar, Prashasti; Agarwal, Pratul K.; Waddell, M. Brett
- Angewandte Chemie, Vol. 131, Issue 45
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- Tabacchi, Gloria; Fabbiani, Marco; Mino, Lorenzo
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- Angewandte Chemie International Edition, Vol. 58, Issue 45
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- Zhou, Shengmin; Wang, Lu
- Physical Chemistry Chemical Physics, Vol. 22, Issue 9
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- Chemical Science, Vol. 10, Issue 33
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