Structural, biochemical and computational studies to study substrate binding and the role of the conserved residues of the DHQ1 (type I dehydroquinase) enzyme active site are reported in the present paper. The crystal structure of DHQ1 from Salmonella typhi in complex with (2R)-2-methyl-3-dehydroquinic acid, a substrate analogue, was solved at 1.5 Å. The present study reveals a previously unknown key role for conserved Glu46, Phe145 and Met205 and Gln236, Pro234 and Ala233 residues, with the latter three being located in the flexible substrate-covering loop. Gln236 was shown to be responsible for the folding of this loop and for the dramatic reduction of its flexibility, which triggers active site closure. Glu46 was found to be key in bringing the substrate close to the lysine/histidine catalytic pocket to initiate catalysis. The present study could be useful in the rational design of inhibitors of this challenging and recognized target for the development of novel herbicides and antimicrobial agents.
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September 2014
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Research Article|
August 22 2014
Insights into substrate binding and catalysis in bacterial type I dehydroquinase
María Maneiro;
María Maneiro
*Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain
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Antonio Peón;
Antonio Peón
*Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain
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Emilio Lence;
Emilio Lence
*Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain
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José M. Otero;
José M. Otero
†Departamento de Bioquímica y Biología Molecular, Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
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Mark J. Van Raaij;
Mark J. Van Raaij
‡Departamento de Estructura de Macromoléculas, Centro Nacional de Biotecnología (CSIC), Campus Cantoblanco, 28049 Madrid, Spain
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Paul Thompson;
Paul Thompson
§Institute of Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, U.K.
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Alastair R. Hawkins;
Alastair R. Hawkins
§Institute of Cell and Molecular Biosciences, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, U.K.
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Concepción González-Bello
Concepción González-Bello
1
*Centro Singular de Investigación en Química Biológica y Materiales Moleculares (CIQUS), Universidad de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain
1To whom correspondence should be addressed (email concepcion.gonzalez.bello@usc.es).
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Publisher: Portland Press Ltd
Received:
May 14 2014
Revision Received:
June 20 2014
Accepted:
June 24 2014
Accepted Manuscript online:
June 24 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 462 (3): 415–424.
Article history
Received:
May 14 2014
Revision Received:
June 20 2014
Accepted:
June 24 2014
Accepted Manuscript online:
June 24 2014
Citation
María Maneiro, Antonio Peón, Emilio Lence, José M. Otero, Mark J. Van Raaij, Paul Thompson, Alastair R. Hawkins, Concepción González-Bello; Insights into substrate binding and catalysis in bacterial type I dehydroquinase. Biochem J 15 September 2014; 462 (3): 415–424. doi: https://doi.org/10.1042/BJ20140614
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