Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states

Banco, Michael T.; Mishra, Vidhi; Ostermann, Andreas; Schrader, Tobias; Evans, Gary B.; Kovalevskyi, Andrii Y.; Ronning, Donald R.

doi:10.1073/pnas.1609718113

Title: Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states

Abstract

MTAN (5'-methylthioadenosine nucleosidase) catalyzes the hydrolysis of the N-ribosidic bond of a variety of adenosine-containing metabolites. The Helicobacter pylori MTAN (HpMTAN) hydrolyzes 6-amino-6-deoxyfutalosine in the second step of the alternative menaquinone biosynthetic pathway. Substrate binding of the adenine moiety is mediated almost exclusively by hydrogen bonds, and the proposed catalytic mechanism requires multiple proton-transfer events. Of particular interest is the protonation state of residue D198, which possesses a pK_a above 8 and functions as a general acid to initiate the enzymatic reaction. In this study we present three corefined neutron/X-ray crystal structures of wild-type HpMTAN cocrystallized with S-adenosylhomocysteine (SAH), Formycin A (FMA), and (3R,4S)-4-(4-Chlorophenylthiomethyl)-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine (p-ClPh-Thio-DADMe-ImmA) as well as one neutron/X-ray crystal structure of an inactive variant (HpMTAN-D198N) cocrystallized with SAH. These results support a mechanism of D198 pKa elevation through the unexpected sharing of a proton with atom N7 of the adenine moiety possessing unconventional hydrogen-bond geometry. Additionally, the neutron structures also highlight active site features that promote the stabilization of the transition state and slight variations in these interactions that result in 100-fold difference in binding affinities between the DADMe-ImmA and ImmA analogs.

Authors:

Banco, Michael T. ^[1]; Mishra, Vidhi ^[1]; Ostermann, Andreas ^[2]; Schrader, Tobias ^[3]; Evans, Gary B. ^[4]; Kovalevskyi, Andrii Y. ^[5]; Ronning, Donald R. ^[1]

Univ. of Toledo, OH (United States)
Technische Univ. Munchen, Garching (Germany)
Julich Research Centre (Germany). Julich Centre for Neutron Science (JCNS)
Victoria Univ. of Wellington (New Zealand)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Publication Date:: Sat Oct 01 00:00:00 EDT 2016

Research Org.:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). High Flux Isotope Reactor (HFIR)

Sponsoring Org.:: USDOE Office of Science (SC)

OSTI Identifier:: 1346637

Grant/Contract Number:: AC05-00OR22725

Resource Type:: Journal Article: Accepted Manuscript

Journal Name:: Proceedings of the National Academy of Sciences of the United States of America (Online)

Additional Journal Information:: Journal Volume: 113; Journal Issue: 48; Journal ID: ISSN 1091-6490

Publisher:: National Academy of Sciences

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES

Citation Formats


                    Banco, Michael T., Mishra, Vidhi, Ostermann, Andreas, Schrader, Tobias, Evans, Gary B., Kovalevskyi, Andrii Y., and Ronning, Donald R. Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states.  United States: N. p., 2016. 
        Web.  doi:10.1073/pnas.1609718113.

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                    Banco, Michael T., Mishra, Vidhi, Ostermann, Andreas, Schrader, Tobias, Evans, Gary B., Kovalevskyi, Andrii Y., & Ronning, Donald R. Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states.  United States.  https://doi.org/10.1073/pnas.1609718113

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                    Banco, Michael T., Mishra, Vidhi, Ostermann, Andreas, Schrader, Tobias, Evans, Gary B., Kovalevskyi, Andrii Y., and Ronning, Donald R. 2016.  
        "Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states".  United States.  https://doi.org/10.1073/pnas.1609718113.  https://www.osti.gov/servlets/purl/1346637.

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@article{osti_1346637,

  title        = {Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states},

  author       = {Banco, Michael T. and Mishra, Vidhi and Ostermann, Andreas and Schrader, Tobias and Evans, Gary B. and Kovalevskyi, Andrii Y. and Ronning, Donald R.},

  abstractNote = {MTAN (5'-methylthioadenosine nucleosidase) catalyzes the hydrolysis of the N-ribosidic bond of a variety of adenosine-containing metabolites. The Helicobacter pylori MTAN (HpMTAN) hydrolyzes 6-amino-6-deoxyfutalosine in the second step of the alternative menaquinone biosynthetic pathway. Substrate binding of the adenine moiety is mediated almost exclusively by hydrogen bonds, and the proposed catalytic mechanism requires multiple proton-transfer events. Of particular interest is the protonation state of residue D198, which possesses a pKa above 8 and functions as a general acid to initiate the enzymatic reaction. In this study we present three corefined neutron/X-ray crystal structures of wild-type HpMTAN cocrystallized with S-adenosylhomocysteine (SAH), Formycin A (FMA), and (3R,4S)-4-(4-Chlorophenylthiomethyl)-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine (p-ClPh-Thio-DADMe-ImmA) as well as one neutron/X-ray crystal structure of an inactive variant (HpMTAN-D198N) cocrystallized with SAH. These results support a mechanism of D198 pKa elevation through the unexpected sharing of a proton with atom N7 of the adenine moiety possessing unconventional hydrogen-bond geometry. Additionally, the neutron structures also highlight active site features that promote the stabilization of the transition state and slight variations in these interactions that result in 100-fold difference in binding affinities between the DADMe-ImmA and ImmA analogs.},

  doi          = {10.1073/pnas.1609718113},

  url          = {https://www.osti.gov/biblio/1346637},
  journal      = {Proceedings of the National Academy of Sciences of the United States of America (Online)},

  issn         = {1091-6490},

  number       = 48,

  volume       = 113,

  place        = {United States},

  year         = {Sat Oct 01 00:00:00 EDT 2016},

  month        = {Sat Oct 01 00:00:00 EDT 2016}

}

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Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states

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Title: Neutron structures of the Helicobacter pylori 5'-methylthioadenosine nucleosidase highlight proton sharing and protonation states

Abstract

Citation Formats

Enzyme-ligand interactions that drive active site rearrangements in the Helicobacter pylori 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase journal, November 2010

New Antibiotic Candidates against Helicobacter pylori journal, November 2015

Crystal Structures of the Helicobacter pylori MTAN Enzyme Reveal Specific Interactions between S -Adenosylhomocysteine and the 5′-Alkylthio Binding Subsite journal, November 2012

Transition State Structure of 5‘-Methylthioadenosine/ S -Adenosylhomocysteine Nucleosidase from Escherichia coli and Its Similarity to Transition State Analogues † journal, September 2005

Conformational Freedom in Tight Binding Enzymatic Transition-State Analogues journal, August 2013

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

A short history of SHELX journal, December 2007

A Picomolar Transition State Analogue Inhibitor of MTAN as a Specific Antibiotic for Helicobacter pylori journal, August 2012

Identification of the Elusive Hydronium Ion Exchanging Roles with a Proton in an Enzyme at Lower pH Values journal, May 2011

Electrostatic Potential Surface Analysis of the Transition State for AMP Nucleosidase and for Formycin 5'-Phosphate, a Transition-State Inhibitor journal, August 1994

Structural enzymology of Helicobacter pylori methylthioadenosine nucleosidase in the futalosine pathway journal, December 2013

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes journal, July 2006

An alternative menaquinone biosynthetic pathway operating in microorganisms: an attractive target for drug discovery to pathogenic Helicobacter and Chlamydia strains journal, June 2009

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Femtomolar Transition State Analogue Inhibitors of 5′-Methylthioadenosine/ S -Adenosylhomocysteine Nucleosidase from Escherichia coli journal, March 2005

Escherichia coli S-adenosylhomocysteine/5′-methylthioadenosine nucleosidase. Purification, substrate specificity and mechanism of action journal, December 1985

Features and development of Coot journal, March 2010

Femtomolar Inhibitors Bind to 5′-Methylthioadenosine Nucleosidases with Favorable Enthalpy and Entropy journal, September 2012

Picomolar Inhibitors as Transition-State Probes of 5′-Methylthioadenosine Nucleosidases journal, November 2007

Direct Measurements of Electric Fields in Weak OH···π Hydrogen Bonds journal, November 2011

Enzyme Homologues Have Distinct Reaction Paths through Their Transition States journal, February 2015

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal, January 2010

Mutational Analysis of a Nucleosidase Involved in Quorum-Sensing Autoinducer-2 Biosynthesis † journal, August 2005

Structural Snapshots of MTA/AdoHcy Nucleosidase Along the Reaction Coordinate Provide Insights into Enzyme and Nucleoside Flexibility During Catalysis journal, September 2005

Structure of Escherichia coli 5′-Methylthioadenosine/ S -Adenosylhomocysteine Nucleosidase Inhibitor Complexes Provide Insight into the Conformational Changes Required for Substrate Binding and Catalysis journal, December 2002

NMRPipe: A multidimensional spectral processing system based on UNIX pipes journal, November 1995

Transition-State Analysis of S. pneumoniae 5‘-Methylthioadenosine Nucleosidase † journal, March 2007

Structure of E. coli 5′-methylthioadenosine/S-adenosylhomocysteine Nucleosidase Reveals Similarity to the Purine Nucleoside Phosphorylases journal, October 2001

Second Generation Transition State Analogue Inhibitors of Human 5‘-Methylthioadenosine Phosphorylase journal, July 2005

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New Antibiotic Candidates against Helicobacter pylori
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journal, November 2012

Transition State Structure of 5‘-Methylthioadenosine/ S -Adenosylhomocysteine Nucleosidase from Escherichia coli and Its Similarity to Transition State Analogues ^†
journal, September 2005

Conformational Freedom in Tight Binding Enzymatic Transition-State Analogues
journal, August 2013

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

A short history of SHELX
journal, December 2007

A Picomolar Transition State Analogue Inhibitor of MTAN as a Specific Antibiotic for Helicobacter pylori
journal, August 2012

Identification of the Elusive Hydronium Ion Exchanging Roles with a Proton in an Enzyme at Lower pH Values
journal, May 2011

Electrostatic Potential Surface Analysis of the Transition State for AMP Nucleosidase and for Formycin 5'-Phosphate, a Transition-State Inhibitor
journal, August 1994

Structural enzymology of Helicobacter pylori methylthioadenosine nucleosidase in the futalosine pathway
journal, December 2013

HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes
journal, July 2006

An alternative menaquinone biosynthetic pathway operating in microorganisms: an attractive target for drug discovery to pathogenic Helicobacter and Chlamydia strains
journal, June 2009

The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli . Chemical evidence for a transition state with a substantial oxocarbenium character
journal, August 1998

Femtomolar Transition State Analogue Inhibitors of 5′-Methylthioadenosine/ S -Adenosylhomocysteine Nucleosidase from Escherichia coli
journal, March 2005

Escherichia coli S-adenosylhomocysteine/5′-methylthioadenosine nucleosidase. Purification, substrate specificity and mechanism of action
journal, December 1985

Features and development of Coot
journal, March 2010

Femtomolar Inhibitors Bind to 5′-Methylthioadenosine Nucleosidases with Favorable Enthalpy and Entropy
journal, September 2012

Picomolar Inhibitors as Transition-State Probes of 5′-Methylthioadenosine Nucleosidases
journal, November 2007

Direct Measurements of Electric Fields in Weak OH···π Hydrogen Bonds
journal, November 2011

Enzyme Homologues Have Distinct Reaction Paths through Their Transition States
journal, February 2015

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

Mutational Analysis of a Nucleosidase Involved in Quorum-Sensing Autoinducer-2 Biosynthesis ^†
journal, August 2005

Structural Snapshots of MTA/AdoHcy Nucleosidase Along the Reaction Coordinate Provide Insights into Enzyme and Nucleoside Flexibility During Catalysis
journal, September 2005

Structure of Escherichia coli 5′-Methylthioadenosine/ S -Adenosylhomocysteine Nucleosidase Inhibitor Complexes Provide Insight into the Conformational Changes Required for Substrate Binding and Catalysis
journal, December 2002

NMRPipe: A multidimensional spectral processing system based on UNIX pipes
journal, November 1995

Transition-State Analysis of S. pneumoniae 5‘-Methylthioadenosine Nucleosidase ^†
journal, March 2007

Structure of E. coli 5′-methylthioadenosine/S-adenosylhomocysteine Nucleosidase Reveals Similarity to the Purine Nucleoside Phosphorylases
journal, October 2001

Second Generation Transition State Analogue Inhibitors of Human 5‘-Methylthioadenosine Phosphorylase
journal, July 2005

Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site
journal, March 2016

Methylthioadenosine/S-adenosylhomocysteine nucleosidase, a critical enzyme for bacterial metabolism: Involvement of MTA/SAH nucleosidase in bacterial metabolism
journal, November 2010

Neutron protein crystallography: current status and a brighter future
journal, October 2006

Structural Rationale for the Affinity of Pico- and Femtomolar Transition State Analogues of Escherichia coli 5′-Methylthioadenosine/ S -Adenosylhomocysteine Nucleosidase
journal, March 2005

Neutron macromolecular crystallography
journal, February 2018

Neutron scattering in the biological sciences: progress and prospects
journal, December 2018