Fluorescent Inhibitors for IspF, an Enzyme in the Non-Mevalonate Pathway for Isoprenoid Biosynthesis and a Potential Target for Antimalarial Therapy

Designed inhibitors (like 1) of IspF, a key enzyme in the non‐mevalonate pathway for terpene biosynthesis and a potential antimalarial target, were synthesized and evaluated. Since fluorescent probes were introduced in these ligands, their affinity towards IspF from E. coli could be determined by fl...

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Published inAngewandte Chemie (International ed.) Vol. 45; no. 7; pp. 1069 - 1074
Main Authors Crane, Christine M., Kaiser, Johannes, Ramsden, Nicola L., Lauw, Susan, Rohdich, Felix, Eisenreich, Wolfgang, Hunter, William N., Bacher, Adelbert, Diederich, François
Format Journal Article
LanguageEnglish
Published Weinheim WILEY-VCH Verlag 06.02.2006
WILEY‐VCH Verlag
Wiley
Subjects
Antimalarials - chemical synthesis
Antimalarials - pharmacology
Binding Sites
Chemistry
Chemistry, Multidisciplinary
Crystallography, X-Ray
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Escherichia coli - drug effects
Escherichia coli Proteins - antagonists & inhibitors
Escherichia coli Proteins - chemistry
fluorescence
Fluorescent Dyes - chemical synthesis
Fluorescent Dyes - pharmacology
inhibitors
IspF
Ligands
Magnetic Resonance Spectroscopy
Models, Molecular
non-mevalonate pathway
Phosphorus-Oxygen Lyases - antagonists & inhibitors
Phosphorus-Oxygen Lyases - chemistry
Physical Sciences
protein crystal structure analysis
Science & Technology
Terpenes - metabolism
inhibitors
IspF
MECHANISM
ESCHERICHIA-COLI
COLI 2C-METHYL-D-ERYTHRITOL-2,4-CYCLODIPHOSPHATE SYNTHASE
IDENTIFICATION
DEOXYXYLULOSE PHOSPHATE-PATHWAY
non-mevalonate pathway
2,4-CYCLODIPHOSPHATE SYNTHASE
fluorescence
FOSMIDOMYCIN
protein crystal structure analysis
BINDING
NONMEVALONATE PATHWAY
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Summary:Designed inhibitors (like 1) of IspF, a key enzyme in the non‐mevalonate pathway for terpene biosynthesis and a potential antimalarial target, were synthesized and evaluated. Since fluorescent probes were introduced in these ligands, their affinity towards IspF from E. coli could be determined by fluorescence titrations. The binding modes of two ligands in ternary complexes with IspF and a ZnII ion were clarified by X‐ray analysis.
Bibliography:We gratefully acknowledge financial support for this work from the following agencies: the Hans-Fischer Gesellschaft e.V. (to J.K.), The Wellcome Trust (to W.N.H.), the Biotechnology and Biological Sciences Research Council (UK) (to W.N.H.), and InPharmatica (to W.N.H.). The authors also thank Prof. D. Arigoni and Dr. L. Kemp for help and advice. IspF=2C-Methyl-D-erythritol 2,4-cyclodiphosphate synthase.
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ArticleID:ANIE200503003
erythritol 2,4‐cyclodiphosphate synthase.
We gratefully acknowledge financial support for this work from the following agencies: the Hans‐Fischer Gesellschaft e.V. (to J.K.), The Wellcome Trust (to W.N.H.), the Biotechnology and Biological Sciences Research Council (UK) (to W.N.H.), and InPharmatica (to W.N.H.). The authors also thank Prof. D. Arigoni and Dr. L. Kemp for help and advice. IspF=2
C
D
Methyl
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.200503003