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Study of Non-Covalent Enzyme-Inhibitor Complexes of Aldose Reductase by Electrospray Mass Spectrometry

Noelle Potier

Laboratoire de Spectrométrie de Masse Bio-Organique, URA 31, CNRS-Université Louis Pasteur, Faculté de chimie, Strasbourg. France

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Patrick Barth,

Patrick Barth

Laboratoire de Chimie Organique Biologique, URA 31, CNRS-Université Louis Pasteur. Faculté de chimie, Strasbourg, France

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Denis Tritsch,

Denis Tritsch

Laboratoire de Chimie Organique Biologique, URA 31, CNRS-Université Louis Pasteur. Faculté de chimie, Strasbourg, France

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Jean-François Biellmann,

Jean-François Biellmann

Laboratoire de Chimie Organique Biologique, URA 31, CNRS-Université Louis Pasteur. Faculté de chimie, Strasbourg, France

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Alain Van Dorsselaer,

Corresponding Author

Alain Van Dorsselaer

Laboratoire de Spectrométrie de Masse Bio-Organique, URA 31, CNRS-Université Louis Pasteur, Faculté de chimie, Strasbourg. France

A. Van Dorsselaer, Laboratoire de Spectrométrie de Masse Bio-Organique, URA 31, CNRS-Université Louis Pasteur, Faculté de chimie, 1 rue Blaise Pascal, F-67008, Strasbourg. France
Fax:+333 88 60 46 87.
E-mail:[email protected]Search for more papers by this author

Noelle Potier,

Noelle Potier

Laboratoire de Spectrométrie de Masse Bio-Organique, URA 31, CNRS-Université Louis Pasteur, Faculté de chimie, Strasbourg. France

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Patrick Barth,

Patrick Barth

Laboratoire de Chimie Organique Biologique, URA 31, CNRS-Université Louis Pasteur. Faculté de chimie, Strasbourg, France

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Denis Tritsch,

Denis Tritsch

Laboratoire de Chimie Organique Biologique, URA 31, CNRS-Université Louis Pasteur. Faculté de chimie, Strasbourg, France

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Jean-François Biellmann,

Jean-François Biellmann

Laboratoire de Chimie Organique Biologique, URA 31, CNRS-Université Louis Pasteur. Faculté de chimie, Strasbourg, France

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Alain Van Dorsselaer,

Corresponding Author

Alain Van Dorsselaer

Laboratoire de Spectrométrie de Masse Bio-Organique, URA 31, CNRS-Université Louis Pasteur, Faculté de chimie, Strasbourg. France

First published: 16 July 2004

https://doi.org/10.1111/j.1432-1033.1997.0274a.x

Citations: 55

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Abstract

Specific non-covalent interactions between aldose reductase (AR), its NADP⁺ cofactor and five inhibitors have been characterized by electrospray mass spectrometry (ES-MS). These results indicated that the protein could be desorbed and maintained in the gas phase in a form very close to its native conformation. Collisionally induced dissociation (CID)-MS and CID-MS-MS showed that the adenosine diphospbate part of the cofactor interacts strongly with AR. The relative stability of the ternary AR NADP⁺ inhibitor complexes was established and successfully correlated with the IC₅₀, values. All inhibitors were shown to only bind to AR holoenzyme. These results are important for the field of drug development insofar as ES-MS might provide a rapid and very sensitive method for the screening of potential drugs or for the identification of compounds displaying high binding affinity to a target biomolecule.

Abbreviations

ES-MS: electrospray mass spectrometry
AR: aldose reductase
CID-MS: collisionally induced dissociation-mass spectrometry
CID-MS-MS: collisionally induced dissociation-mass spectrometry-mass spectrometry
FTICR: Fourier-transform ion-cyclotron resonance
ADP-RibP.: 2′-monophosphoadenosine-5′-diphosphoribose
IC₅₀: concentration of inhibitor required to produce 50% inhibition of enzyme activity
IE₅₀: number of equivalent of inhibitor leading to a decrease of 50% of enzyme activity

Enzymes

: Aldose reductase (E. C. 1.1.1.21)
: yeast alcohol dehydrogenase (E. C. 1.1.1.1)

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Volume243, Issue1-2

January 1997

Pages 274-282

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Study of Non-Covalent Enzyme-Inhibitor Complexes of Aldose Reductase by Electrospray Mass Spectrometry

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Study of Non-Covalent Enzyme-Inhibitor Complexes of Aldose Reductase by Electrospray Mass Spectrometry

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