Browse by author
Lookup NU author(s): Paul Thompson,
Professor Alastair Hawkins
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
The phosphoryl-transfer mechanism of shikimate kinase from Mycobacterium tuberculosis and Helicobacter pylori, which is an attractive target for antibiotic drug discovery, has been studied by 1D H-1 and (PNMR)-P-31 spectroscopy. Metaphosphoric acid proved to be a good mimetic of the metaphosphate intermediate and facilitated the ready and rapid evaluation by NMR spectroscopic analysis of a dissociative mechanism. The required closed form of the active site for catalysis was achieved by the use of ADP (product) or two synthetic ADP analogues (AMPNP, AMPCP). Molecular dynamics simulation studies reported here also revealed that the essential arginine (Arg116/Arg117 in H. pylori and M. tuberculosis, respectively), which activates the -phosphate group of ATP for catalysis and triggers the release of the product for turnover, would also be involved in the stabilisation of the metaphosphate intermediate during catalysis. We believe that the studies reported here will be helpful for future structure-based design of inhibitors of this attractive target. The approach is also expected be useful for studies on the possible dissociative mechanism of other kinase enzymes.
Author(s): Prado V, Lence E, Vallejo JA, Beceiro A, Thompson P, Hawkins AR, Gonzalez-Bello C
Publication type: Article
Publication status: Published
Journal: Chemistry: A European Journal
Print publication date: 01/02/2016
Online publication date: 21/01/2016
Acceptance date: 01/01/1900
ISSN (print): 0947-6539
ISSN (electronic): 1521-3765
Publisher: Wiley - V C H Verlag GmbH & Co. KGaA
Altmetrics provided by Altmetric