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Title: Crystal Structures of An F420-Dependent Glucose-6-Phosphate Dehydrogenase Fgd1 Involved in the Activation of the Anti-Tb Drug Candidate Pa-824 Reveal the Basis of Coenzyme And Substrate Binding

Abstract

The modified flavin coenzyme F{sub 420} is found in a restricted number of microorganisms. It is widely distributed in mycobacteria, however, where it is important in energy metabolism, and in Mycobacterium tuberculosis (Mtb) is implicated in redox processes related to non-replicating persistence. In Mtb, the F{sub 420}-dependent glucose-6-phosphate dehydrogenase FGD1 provides reduced F{sub 420} for the in vivo activation of the nitroimidazopyran prodrug PA-824, currently being developed for anti-tuberculosis therapy against both replicating and persistent bacteria. The structure of M. tuberculosis FGD1 has been determined by x-ray crystallography both in its apo state and in complex with F{sub 420} and citrate at resolutions of 1.90 and 1.95{angstrom}, respectively. The structure reveals a highly specific F{sub 420} binding mode, which is shared with several other F{sub 420}-dependent enzymes. Citrate occupies the substrate binding pocket adjacent to F{sub 420} and is shown to be a competitive inhibitor (IC{sub 50} 43 {micro}m). Modeling of the binding of the glucose 6-phosphate (G6P) substrate identifies a positively charged phosphate binding pocket and shows that G6P, like citrate, packs against the isoalloxazine moiety of F{sub 420} and helps promote a butterfly bend conformation that facilitates F{sub 420} reduction and catalysis.

Authors:
; ; ;
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
958631
Report Number(s):
SLAC-REPRINT-2009-058
Journal ID: ISSN 0021-9258; JBCHA3; TRN: US201001%%779
DOE Contract Number:  
AC02-76SF00515
Resource Type:
Journal Article
Journal Name:
J. Biol. Chem 283:17531,2008
Additional Journal Information:
Journal Volume: 283; Journal Issue: 25; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; BACTERIA; CATALYSIS; CITRATES; COENZYMES; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; ENZYMES; GLUCOSE; IN VIVO; ISOALLOXAZINES; METABOLISM; MICROORGANISMS; MYCOBACTERIUM TUBERCULOSIS; OXIDOREDUCTASES; PHOSPHATES; SUBSTRATES; THERAPY; TUBERCULOSIS; Other,OTHER, BIO, CHEM

Citation Formats

Bashiri, G, Squire, C J, Moreland, N J, and Baker, E N. Crystal Structures of An F420-Dependent Glucose-6-Phosphate Dehydrogenase Fgd1 Involved in the Activation of the Anti-Tb Drug Candidate Pa-824 Reveal the Basis of Coenzyme And Substrate Binding. United States: N. p., 2009. Web.
Bashiri, G, Squire, C J, Moreland, N J, & Baker, E N. Crystal Structures of An F420-Dependent Glucose-6-Phosphate Dehydrogenase Fgd1 Involved in the Activation of the Anti-Tb Drug Candidate Pa-824 Reveal the Basis of Coenzyme And Substrate Binding. United States.
Bashiri, G, Squire, C J, Moreland, N J, and Baker, E N. 2009. "Crystal Structures of An F420-Dependent Glucose-6-Phosphate Dehydrogenase Fgd1 Involved in the Activation of the Anti-Tb Drug Candidate Pa-824 Reveal the Basis of Coenzyme And Substrate Binding". United States.
@article{osti_958631,
title = {Crystal Structures of An F420-Dependent Glucose-6-Phosphate Dehydrogenase Fgd1 Involved in the Activation of the Anti-Tb Drug Candidate Pa-824 Reveal the Basis of Coenzyme And Substrate Binding},
author = {Bashiri, G and Squire, C J and Moreland, N J and Baker, E N},
abstractNote = {The modified flavin coenzyme F{sub 420} is found in a restricted number of microorganisms. It is widely distributed in mycobacteria, however, where it is important in energy metabolism, and in Mycobacterium tuberculosis (Mtb) is implicated in redox processes related to non-replicating persistence. In Mtb, the F{sub 420}-dependent glucose-6-phosphate dehydrogenase FGD1 provides reduced F{sub 420} for the in vivo activation of the nitroimidazopyran prodrug PA-824, currently being developed for anti-tuberculosis therapy against both replicating and persistent bacteria. The structure of M. tuberculosis FGD1 has been determined by x-ray crystallography both in its apo state and in complex with F{sub 420} and citrate at resolutions of 1.90 and 1.95{angstrom}, respectively. The structure reveals a highly specific F{sub 420} binding mode, which is shared with several other F{sub 420}-dependent enzymes. Citrate occupies the substrate binding pocket adjacent to F{sub 420} and is shown to be a competitive inhibitor (IC{sub 50} 43 {micro}m). Modeling of the binding of the glucose 6-phosphate (G6P) substrate identifies a positively charged phosphate binding pocket and shows that G6P, like citrate, packs against the isoalloxazine moiety of F{sub 420} and helps promote a butterfly bend conformation that facilitates F{sub 420} reduction and catalysis.},
doi = {},
url = {https://www.osti.gov/biblio/958631}, journal = {J. Biol. Chem 283:17531,2008},
issn = {0021-9258},
number = 25,
volume = 283,
place = {United States},
year = {Mon May 11 00:00:00 EDT 2009},
month = {Mon May 11 00:00:00 EDT 2009}
}