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Understanding the key factors that control the inhibition of type II dehydroquinase by (2R)-2-benzyl-3-dehydroquinic acids

Lookup NU author(s): Dr Heather Lamb, Professor Alastair Hawkins


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The binding mode of several substrate analogues, (2R)-2-benzyl-3- dehydroquinic acids 4, which are potent reversible competitive inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway, has been investigated by structural and computational studies. The crystal structures of Mycobacterium tuberculosis and Helicobacter pylori DHQ2 in complex with one of the most potent inhibitor, p-methoxybenzyl derivative 4a, have been solved at 2.40 Å and 2.75 Å, respectively. This has allowed the resolution of the M. tuberculosis DHQ2 loop containing residues 20-25 for the first time. These structures show the key interactions of the aromatic ring in the active site of both enzymes and additionally reveal an important change in the conformation and flexibility of the loop that closes over substrate binding. The loop conformation and the binding mode of compounds 4b-d has been also studied by molecular dynamics simulations, which suggest that the benzyl group of inhibitors 4 prevent appropriate orientation of the catalytic tyrosine of the loop for proton abstraction and disrupts its basicity. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Publication metadata

Author(s): Peón A, Otero J, Tizón L, Prazeres V, Llamas-Saiz A, Fox G, Van Raaij M, Lamb H, Hawkins A, Gago F, Castedo L, González-Bello C

Publication type: Article

Publication status: Published

Journal: ChemMedChem

Year: 2010

Volume: 5

Issue: 10

Pages: 1726-1733

Print publication date: 02/09/2010

ISSN (print): 1860-7179

ISSN (electronic): 1860-7187

Publisher: Wiley - VCH Verlag GmbH & Co. KGaA


DOI: 10.1002/cmdc.201000281


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Funder referenceFunder name
Portuguese Fundacao para a Ciencia e a Tecnologia
BFU2005-02974/BMCSpanish Ministry of Science and Innovation
BFU2008-01588/BMCSpanish Ministry of Science and Innovation
GRC2006/132Xunta de Galicia
PGIDT07PXIB209080PRXunta de Galicia
SAF2007-63533Spanish Ministry of Science and Innovation