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  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

Bauer, H., Fritz-Wolf, K., Winzer, A., Kühner, S., Little, S., Yardley, V., et al. (2006). 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. Journal of the American Chemical Society, 128(33), 10784-10794. doi:10.1021/ja061155v.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-E160-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0001-E161-3
Genre: Journal Article

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 Creators:
Bauer, Holger, Author
Fritz-Wolf, Karin1, Author              
Winzer, Andreas, Author
Kühner, Sebastian, Author
Little, Susan, Author
Yardley, Vanessa, Author
Vezin, Hervé, Author
Palfey, Bruce, Author
Schirmer, R. Heiner, Author
Davioud−Charvet, Elisabeth, Author
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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 Abstract: 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 M(5), 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-M(5) 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 k(inact) value of 0.4 +/- 0.2 min(-1). The crystal structure of the alkylated enzyme was solved at 1.7 A 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.

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Language(s): eng - English
 Dates: 2006-02-272006-07-282006-08-23
 Publication Status: Published in print
 Pages: 11
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 Rev. Type: Peer
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Title: Journal of the American Chemical Society
  Other : J. Am. Chem. Soc.
  Abbreviation : JACS
Source Genre: Journal
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Publ. Info: American Chemical Society
Pages: - Volume / Issue: 128 (33) Sequence Number: - Start / End Page: 10784 - 10794 Identifier: ISSN: 0002-7863
CoNE: https://pure.mpg.de/cone/journals/resource/954925376870