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Pseudilins : halogenated, allosteric inhibitors of the non-mevalonate pathway enzyme IspD

Kunfermann, Andrea and Witschel, Matthias and Illarionov, Boris and Martin, René and Rottmann, Matthias and Höffken, H. Wolfgang and Seet, Michael and Eisenreich, Wolfgang and Knölker, Hans-Joachim and Fischer, Markus and Bacher, Adelbert and Groll, Michael and Diederich, François. (2014) Pseudilins : halogenated, allosteric inhibitors of the non-mevalonate pathway enzyme IspD. Angewandte Chemie. International edition in English, Vol. 53, H. 8. pp. 2235-2239.

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Official URL: http://edoc.unibas.ch/dok/A6271940

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Abstract

The enzymes of the non-mevalonate pathway for isoprenoid biosynthesis have been identified as attractive targets with novel modes of action for the development of herbicides for crop protection and agents against infectious diseases. This pathway is present in many pathogenic organisms and plants, but absent in mammals. By using high-throughput screening, we identified highly halogenated marine natural products, the pseudilins, to be inhibitors of the third enzyme, IspD, in the pathway. Their activity against the IspD enzymes from Arabidopsis thaliana and Plasmodium vivax was determined in photometric and NMR-based assays. Cocrystal structures revealed that pseudilins bind to an allosteric pocket by using both divalent metal ion coordination and halogen bonding. The allosteric mode of action for preventing cosubstrate (CTP) binding at the active site was elucidated. Pseudilins show herbicidal activity in plant assays and antiplasmodial activity in cell-based assays.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:VCH
ISSN:1521-3773
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:15 Aug 2014 07:16
Deposited On:15 Aug 2014 07:16

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