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          Institute: MPI für medizinische Forschung     Collection: Abteilung Organische Chemie     Display Documents



ID: 568575.0, MPI für medizinische Forschung / Abteilung Organische Chemie
A Fluoro Analogue of the Menadione Derivative 6−[2‘−(3‘−Methyl)−1‘,4‘−naphthoquinolyl]hexanoic Acid Is a Suicide Substrate of Glutathione Reductase. Crystal Structure of the Alkylated Human Enzyme
Translation of Title:A Fluoro Analogue of the Menadione Derivative 6−[2‘−(3‘−Methyl)−1‘,4‘−naphthoquinolyl]hexanoic Acid Is a Suicide Substrate of Glutathione Reductase. Crystal Structure of the Alkylated Human Enzyme
Authors:Bauer, Helmut; Fritz−Wolf, Karin; Winzer, Andreas; Kühner, Sebastian; Little, Susan; Yardley, Vanessa; Vezin, Hervé; Palfey, Bruce; Schirmer, R. Heiner; Davioud−Charvet, Elisabeth
Language:English
Date of Publication (YYYY-MM-DD):2006-07-28
Title of Journal:Journal of the American Chemical Society
Journal Abbrev.:J. Am. Chem. Soc.
Volume:128
Issue / Number:33
Start Page:10784
End Page:10794
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:Glutathione reductase is an important housekeeping enzyme for redox homeostasis both in human cells and in the causative agent of tropical malaria, Plasmodium falciparum. Glutathione reductase inhibitors were shown to have anticancer and antimalarial activity per se and to contribute to the reversal of drug resistance. The development of menadione chemistry has led to the selection of 6−[2‘−(3‘−methyl)−1‘,4‘−naphthoquinolyl]hexanoic acid, called M5,as a potent reversible and uncompetitive inhibitor of both human and P. falciparum glutathione reductases. Here we describe the synthesis and kinetic characterization of a fluoromethyl−M5 analogue that acts as a mechanism−based inhibitor of both enzymes. In the course of enzymatic catalysis, the suicide substrate is activated by one− or two−electron reduction, and then a highly reactive quinone methide is generated upon elimination of the fluorine. Accordingly the human enzyme was found to be irreversibly inactivated with a kinact value of 0.4 ± 0.2 min−1. The crystal structure of the alkylated enzyme was solved at 1.7 Å resolution. It showed the inhibitor to bind covalently to the active site Cys58 and to interact noncovalently with His467‘, Arg347, Arg37, and Tyr114. On the basis of the crystal structure of the inactivated human enzyme and stopped−flow kinetic studies with two− and four−electron−reduced forms of the unreacted P. falciparum enzyme, a mechanism is proposed which explains naphthoquinone reduction at the flavin of glutathione reductase
Last Change of the Resource (YYYY-MM-DD):--
External Publication Status:published
Document Type:Article
Communicated by:Wulf Kaiser
Affiliations:MPI für medizinische Forschung/Abteilung Biophysik
MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen
MPI für medizinische Forschung/Emeritus - Gruppe Organische Chemie
Identifiers:LOCALID:7640
URI:http%3A%2F%2Fpubs.acs.org%2Fdoi%2Fpdfplus%2F10.102...
URI:http%3A%2F%2Fpubs.acs.org%2Fdoi%2Ffull%2F10.1021%2...
URI:http%3A%2F%2Fpubs.acs.org%2Fdoi%2Fabs%2F10.1021%2F...
DOI:10.1021%2Fja061155v
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