English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
 
 
DownloadE-Mail
 Local TagsRelease HistoryDetailsSummary
  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.

Item is

 

show all hide all

Basic

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

Files

show Files
hide Files
:
JACS_128_2006_10784.pdf (Any fulltext), 329KB
 
File Permalink:
-
Name:
JACS_128_2006_10784.pdf
Description:
-
OA-Status:
Visibility:
Restricted (Max Planck Institute for Medical Research, MHMF; )
MIME-Type / Checksum:
application/pdf
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
JACS_128_2006_10784_Suppl1.pdf (Supplementary material), 301KB
 
File Permalink:
-
Name:
JACS_128_2006_10784_Suppl1.pdf
Description:
-
OA-Status:
Visibility:
Restricted (Max Planck Institute for Medical Research, MHMF; )
MIME-Type / Checksum:
application/pdf
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-
:
JACS_128_2006_10784_Suppl2.pdf (Supplementary material), 303KB
 
File Permalink:
-
Name:
JACS_128_2006_10784_Suppl2.pdf
Description:
-
OA-Status:
Visibility:
Restricted (Max Planck Institute for Medical Research, MHMF; )
MIME-Type / Checksum:
application/pdf
Technical Metadata:
Copyright Date:
-
Copyright Info:
-
License:
-

Locators

show
hide
Locator:
https://pubs.acs.org/doi/pdf/10.1021/ja061155v (Any fulltext)
Description:
-
OA-Status:
Locator:
https://pubs.acs.org/doi/suppl/10.1021/ja061155v/suppl_file/ja061155v.pdf (Supplementary material)
Description:
-
OA-Status:
Locator:
https://pubs.acs.org/doi/suppl/10.1021/ja061155v/suppl_file/ja061155vsi20060707_121750.pdf (Supplementary material)
Description:
-
OA-Status:
Locator:
https://doi.org/10.1021/ja061155v (Any fulltext)
Description:
-
OA-Status:

Creators

show
hide
 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              

Content

show
hide
Free keywords: -
 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.

Details

show
hide
Language(s): eng - English
 Dates: 2006-02-272006-07-282006-08-23
 Publication Status: Issued
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/ja061155v
URI: http://www.ncbi.nlm.nih.gov/pubmed/16910673
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Journal of the American Chemical Society
  Other : J. Am. Chem. Soc.
  Abbreviation : JACS
Source Genre: Journal
 Creator(s):
Affiliations:
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