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/ange.201908535

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

Abstract

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.

Authors:

^[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

Publication Date:: Tue Sep 24 00:00:00 EDT 2019

Sponsoring Org.:: USDOE

OSTI Identifier:: 1566163

Grant/Contract Number:: FWP ERKP291

Resource Type:: Publisher's Accepted Manuscript

Journal Name:: Angewandte Chemie

Additional Journal Information:: Journal Name: Angewandte Chemie Journal Volume: 131 Journal Issue: 45; Journal ID: ISSN 0044-8249

Publisher:: Wiley Blackwell (John Wiley & Sons)

Country of Publication:: Germany

Language:: English

Citation Formats


                    Kumar, Prashasti, Agarwal, Pratul K., Waddell, M. Brett, Mittag, Tanja, Serpersu, Engin H., and Cuneo, Matthew J. Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad.  Germany: N. p., 2019. 
Web.  doi:10.1002/ange.201908535.

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                    Kumar, Prashasti, Agarwal, Pratul K., Waddell, M. Brett, Mittag, Tanja, Serpersu, Engin H., & Cuneo, Matthew J. Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad.  Germany.  https://doi.org/10.1002/ange.201908535

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                    Kumar, Prashasti, Agarwal, Pratul K., Waddell, M. Brett, Mittag, Tanja, Serpersu, Engin H., and Cuneo, Matthew J. Tue .  
"Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad".  Germany.  https://doi.org/10.1002/ange.201908535.

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@article{osti_1566163,

  title        = {Low‐Barrier and Canonical Hydrogen Bonds Modulate Activity and Specificity of a Catalytic Triad},

  author       = {Kumar, Prashasti and Agarwal, Pratul K. and Waddell, M. Brett and Mittag, Tanja and Serpersu, Engin H. and Cuneo, Matthew J.},

  abstractNote = {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.},

  doi          = {10.1002/ange.201908535},

  journal      = {Angewandte Chemie},

  number       = 45,

  volume       = 131,

  place        = {Germany},

  year         = {Tue Sep 24 00:00:00 EDT 2019},

  month        = {Tue Sep 24 00:00:00 EDT 2019}

}

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

Abstract

Citation Formats

Subangstrom Crystallography Reveals that Short Ionic Hydrogen Bonds, and Not a His-Asp Low-Barrier Hydrogen Bond, Stabilize the Transition State in Serine Protease Catalysis journal, July 2006

Electrostatic Interactions Guide the Active Site Face of a Structure-Specific Ribonuclease to Its RNA Substrate † journal, August 2008

Structural Basis of Perturbed pKa Values of Catalytic Groups in Enzyme Active Sites journal, February 2002

An explanation for rapid enzyme-catalyzed proton abstraction from carbon acids: importance of late transition states in concerted mechanisms journal, December 1993

Plasticity of enzyme active sites journal, August 2002

Short strong hydrogen bonds: can they explain enzymic catalysis? journal, March 1996

Protonation-State Dependence of Hydrogen Bond Strengths and Exchange Rates in a Serine Protease Catalytic Triad: Bovine Chymotrypsinogen A † journal, January 1996

Ladungen verschieben Protonierungen: Neutronenbeugung zeigt, dass Anilin und 2-Aminopyridin protoniert an Trypsin binden journal, March 2017

Electrostatic effects in proteins journal, September 1978

Encoding of Promiscuity in an Aminoglycoside Acetyltransferase journal, October 2018

A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad journal, April 2018

Aminoglycoside 2′-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates journal, August 2002

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BIOCHEMISTRY: How Enzymes Work journal, June 2008

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Interactions of Coenzyme A with the Aminoglycoside Acetyltransferase (3)-IIIb and Thermodynamics of a Ternary System journal, May 2010

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Hydrogen Bonding at the Active Site of Δ 5 -3-Ketosteroid Isomerase † journal, December 1997

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Low-barrier hydrogen bonds and enzymic catalysis journal, June 1994

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Thermodynamics of Aminoglycoside Binding to Aminoglycoside-3‘-phosphotransferase IIIa Studied by Isothermal Titration Calorimetry † journal, November 2004

Long-range Electrostatic Complementarity Governs Substrate Recognition by Human Chymotrypsin C, a Key Regulator of Digestive Enzyme Activation journal, February 2013

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

Electrostatic Origin of the Catalytic Power of Enzymes and the Role of Preorganized Active Sites journal, October 1998

Solid State NMR Studies of Hydrogen Bonding in a Citrate Synthase Inhibitor Complex † journal, June 1999

Probing Electrostatic Interactions along the Reaction Pathway of a Glycoside Hydrolase: Histidine Characterization by NMR Spectroscopy † journal, June 2007

On low-barrier hydrogen bonds and enzyme catalysis journal, July 1995

Subangstrom Crystallography Reveals that Short Ionic Hydrogen Bonds, and Not a His-Asp Low-Barrier Hydrogen Bond, Stabilize the Transition State in Serine Protease Catalysis
journal, July 2006

Electrostatic Interactions Guide the Active Site Face of a Structure-Specific Ribonuclease to Its RNA Substrate ^†
journal, August 2008

Structural Basis of Perturbed pKa Values of Catalytic Groups in Enzyme Active Sites
journal, February 2002

An explanation for rapid enzyme-catalyzed proton abstraction from carbon acids: importance of late transition states in concerted mechanisms
journal, December 1993

Plasticity of enzyme active sites
journal, August 2002

Short strong hydrogen bonds: can they explain enzymic catalysis?
journal, March 1996

Protonation-State Dependence of Hydrogen Bond Strengths and Exchange Rates in a Serine Protease Catalytic Triad: Bovine Chymotrypsinogen A ^†
journal, January 1996

Ladungen verschieben Protonierungen: Neutronenbeugung zeigt, dass Anilin und 2-Aminopyridin protoniert an Trypsin binden
journal, March 2017

Electrostatic effects in proteins
journal, September 1978

Encoding of Promiscuity in an Aminoglycoside Acetyltransferase
journal, October 2018

A low-barrier hydrogen bond mediates antibiotic resistance in a noncanonical catalytic triad
journal, April 2018

Aminoglycoside 2′-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates
journal, August 2002

Protein Dynamics Are Influenced by the Order of Ligand Binding to an Antibiotic Resistance Enzyme
journal, December 2013

BIOCHEMISTRY: How Enzymes Work
journal, June 2008

A low-barrier hydrogen bond in the catalytic triad of serine proteases
journal, June 1994

The Low Barrier Hydrogen Bond in Enzymatic Catalysis
journal, October 1998

Interactions of Coenzyme A with the Aminoglycoside Acetyltransferase (3)-IIIb and Thermodynamics of a Ternary System
journal, May 2010

X-ray Snapshot of HIV-1 Protease in Action: Observation of Tetrahedral Intermediate and Short Ionic Hydrogen Bond SIHB with Catalytic Aspartate
journal, May 2010

Hydrogen Bonding at the Active Site of Δ ⁵ -3-Ketosteroid Isomerase ^†
journal, December 1997

Ligand promiscuity through the eyes of the aminoglycoside N 3 acetyltransferase IIa : Molecular Basis of Ligand Promiscuity
journal, June 2013

Direct evidence that an extended hydrogen-bonding network influences activation of pyridoxal 5′-phosphate in aspartate aminotransferase
journal, February 2017

Low-barrier hydrogen bonds and enzymic catalysis
journal, June 1994

The low barrier hydrogen bond (LBHB) proposal revisited: The case of the Asp ··· His pair in serine proteases
journal, April 2004

Thermodynamics of an aminoglycoside modifying enzyme with low substrate promiscuity: The aminoglycoside N3 acetyltransferase-VIa : Thermodynamic Basis of Ligand Promiscuity
journal, March 2017

Thermodynamics and Kinetics of Association of Antibiotics with the Aminoglycoside Acetyltransferase (3)-IIIb, a Resistance-Causing Enzyme
journal, May 2010

Charges Shift Protonation: Neutron Diffraction Reveals that Aniline and 2-Aminopyridine Become Protonated Upon Binding to Trypsin
journal, March 2017

Thermodynamics of Aminoglycoside Binding to Aminoglycoside-3‘-phosphotransferase IIIa Studied by Isothermal Titration Calorimetry ^†
journal, November 2004

Long-range Electrostatic Complementarity Governs Substrate Recognition by Human Chymotrypsin C, a Key Regulator of Digestive Enzyme Activation
journal, February 2013

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

Electrostatic Origin of the Catalytic Power of Enzymes and the Role of Preorganized Active Sites
journal, October 1998

Solid State NMR Studies of Hydrogen Bonding in a Citrate Synthase Inhibitor Complex ^†
journal, June 1999

Probing Electrostatic Interactions along the Reaction Pathway of a Glycoside Hydrolase: Histidine Characterization by NMR Spectroscopy ^†
journal, June 2007

On low-barrier hydrogen bonds and enzyme catalysis
journal, July 1995