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Insights into substrate binding and catalysis in bacterial type I dehydroquinase

Lookup NU author(s): Paul Thompson, Professor Alastair Hawkins

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Abstract

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 angstrom. The present study reveals a previously unknown key role for conserved Glu(46), Phe(145) and Met(205) and Gln(236), Pro(234) and Ala(233) residues, with the latter three being located in the flexible substrate-covering loop. Gln(236) was shown to be responsible for the folding of this loop and for the dramatic reduction of its flexibility, which triggers active site closure. Glu(46) 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.

Publication metadata

Author(s): Maneiro M, Peon A, Lence E, Otero JM, Van Raaij MJ, Thompson P, Hawkins AR, Gonzalez-Bello C

Publication type: Article

Publication status: Published

Journal: Biochemical Journal

Year: 2014

Volume: 462

Pages: 415-424

Print publication date: 15/09/2014

Online publication date: 24/06/2014

Acceptance date: 24/06/2014

ISSN (print): 0264-6021

ISSN (electronic): 1470-8728

Publisher: Portland Press Ltd.

URL: http://dx.doi.org/10.1042/BJ20140614

DOI: 10.1042/BJ20140614

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