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Structural Basis of Fosmidomycin Action Revealed by the Complex with 2-C-Methyl-D-erythritol 4-phosphate Synthase (IspC): implications for the catalytic mechanism and anti-malaria drug development

Steinbacher, Stefan and Kaiser, Johannes and Eisenreich, Wolfgang and Huber, Robert and Bacher, Adelbert and Rohdich, Felix (2003) Structural Basis of Fosmidomycin Action Revealed by the Complex with 2-C-Methyl-D-erythritol 4-phosphate Synthase (IspC): implications for the catalytic mechanism and anti-malaria drug development. Journal of Biological Chemistry, 278 (20). pp. 18401-18407. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:STEjbc03b

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Abstract

2-C-Methyl-D-erythritol 4-phosphate synthase (IspC) is the first enzyme committed to isoprenoid biosynthesis in the methylerythritol phosphate pathway, which represents an alternative route to the classical mevalonate pathway. As it is present in many pathogens and plants, but not in man, this pathway has attracted considerable interest as a target for novel antibiotics and herbicides. Fosmidomycin represents a specific high-affinity inhibitor of IspC. Very recently, its anti-malaria activity in man has been demonstrated in clinical trials. Here, we present the crystal structure of Escherichia coli IspC in complex with manganese and fosmidomycin at 2.5 Å resolution. The (N-formyl-N-hydroxy)amino group provides two oxygen ligands to manganese that is present in a distorted octahedral coordination, whereas the phosphonate group is anchored in a specific pocket by numerous hydrogen bonds. Both sites are connected by a spacer of three methylene groups. The substrate molecule, 1-D-deoxyxylulose 5-phosphate, can be superimposed onto fosmidomycin, explaining the stereochemical course of the reaction.


Item Type:Article
Additional Information:Copyright © 2003 by the American Society for Biochemistry and Molecular Biology. Received for publication, January 29, 2003, and in revised form, March 4, 2003. Originally published In Press as doi:10.1074/jbc.M300993200 on March 5, 2003. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The atomic coordinates and the structure factors (code 1ONN, 1ONO, and 1ONP) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
Record Number:CaltechAUTHORS:STEjbc03b
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:STEjbc03b
Alternative URL:http://dx.doi.org/10.1074/jbc.M300993200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:9229
Collection:CaltechAUTHORS
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Deposited On:28 Nov 2007
Last Modified:26 Dec 2012 09:46

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