Structures of coenzyme F 420 in Mycobacterium species

Bair, Thomas B.; Isabelle, Dale W.; Daniels, Lacy

doi:10.1007/s002030100290

Cited by 51 publications

(48 citation statements)

References 20 publications

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“…Analysis by MALDI-TOF mass spectrometry shows that the F 420 isolated from M. smegmatis contains up to nine glutamate residues, although the predominant species has six (Fig. 2), in line with previously published analyses which indicated five or six glutamates (32).…”

Section: Resultssupporting

confidence: 90%

Crystal Structures of F420-dependent Glucose-6-phosphate Dehydrogenase FGD1 Involved in the Activation of the Anti-tuberculosis Drug Candidate PA-824 Reveal the Basis of Coenzyme and Substrate Binding

Bashiri

Squire

Moreland

et al. 2008

Journal of Biological Chemistry

150

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The modified flavin coenzyme F 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 420 -dependent glucose-6-phosphate dehydrogenase FGD1 provides reduced F 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 420 and citrate at resolutions of 1.90 and 1.95 Å , respectively. The structure reveals a highly specific F 420 binding mode, which is shared with several other F 420 -dependent enzymes. Citrate occupies the substrate binding pocket adjacent to F 420 and is shown to be a competitive inhibitor (IC 50 43 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 420 and helps promote a butterfly bend conformation that facilitates F 420 reduction and catalysis.

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Section: Resultssupporting

confidence: 90%

Crystal Structures of F420-dependent Glucose-6-phosphate Dehydrogenase FGD1 Involved in the Activation of the Anti-tuberculosis Drug Candidate PA-824 Reveal the Basis of Coenzyme and Substrate Binding

Bashiri

Squire

Moreland

et al. 2008

Journal of Biological Chemistry

150

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“…It is proposed that the cofactor is activated by phosphorylation (at the terminal hydroxyl group of the lactate moiety of F 420 and the terminal glutamate of F 420 -n derivatives), and the resultant acyl-phosphate is subject to nucleophilic attack by the amino group of the incoming glutamate residue (123). The number of glutamate residues on F 420 is highly species specific, ranging from two or three in methanogens without cytochromes (124), four or five in methano- gens with cytochromes (124), and five to seven in mycobacteria (125). The physiological significance and biochemical basis for these differences is not yet understood.…”

Section: Biosynthesismentioning

confidence: 99%

“…It is assumed that F 420 has a more restricted distribution among bacteria. The cofactor has been identified in representatives of the actinobacterial genera Mycobacterium (23,27,125,145), Streptomyces (25,27,29,146), Nocardia (27,145), and Nocardioides (54). Most of these representatives are saprophytic soil bacteria that adopt a heterotrophic, aerobic lifestyle.…”

Section: Distributionmentioning

confidence: 99%

Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

Greening

Ahmed

Mohamed

et al. 2016

Microbiol Mol Biol Rev

152

208

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SUMMARY5-Deazaflavin cofactors enhance the metabolic flexibility of microorganisms by catalyzing a wide range of challenging enzymatic redox reactions. While structurally similar to riboflavin, 5-deazaflavins have distinctive and biologically useful electrochemical and photochemical properties as a result of the substitution of N-5 of the isoalloxazine ring for a carbon. 8-Hydroxy-5-deazaflavin (Fo) appears to be used for a single function: as a light-harvesting chromophore for DNA photolyases across the three domains of life. In contrast, its oligoglutamyl derivative F420is a taxonomically restricted but functionally versatile cofactor that facilitates many low-potential two-electron redox reactions. It serves as an essential catabolic cofactor in methanogenic, sulfate-reducing, and likely methanotrophic archaea. It also transforms a wide range of exogenous substrates and endogenous metabolites in aerobic actinobacteria, for example mycobacteria and streptomycetes. In this review, we discuss the physiological roles of F420in microorganisms and the biochemistry of the various oxidoreductases that mediate these roles. Particular focus is placed on the central roles of F420in methanogenic archaea in processes such as substrate oxidation, C1pathways, respiration, and oxygen detoxification. We also describe how two F420-dependent oxidoreductase superfamilies mediate many environmentally and medically important reactions in bacteria, including biosynthesis of tetracycline and pyrrolobenzodiazepine antibiotics by streptomycetes, activation of the prodrugs pretomanid and delamanid byMycobacterium tuberculosis, and degradation of environmental contaminants such as picrate, aflatoxin, and malachite green. The biosynthesis pathways of Foand F420are also detailed. We conclude by considering opportunities to exploit deazaflavin-dependent processes in tuberculosis treatment, methane mitigation, bioremediation, and industrial biocatalysis.

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“…Bioreductive activation of PA-824 has been shown to depend on Rv0407, which encodes an F 420 -dependent, glucose-6-phosphate dehydrogenase (FGD1) (6). Cofactor F 420 has 7,8-didemethyl-8-hydroxy-5-deazariboflavin, a phospholactyl moiety, and a variable number (two to six) of glutamate residues (8). F 420 has a limited distribution among the archaea and GC-rich Grampositive bacteria, shows a low redox potential (EЈ ϭ Ϫ350 mV), and functions as a two-electron redox-carrier coenzyme (9).…”

mentioning

confidence: 99%

Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis

Manjunatha

Boshoff

Dowd

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

310

278

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PA-824 is a promising new compound for the treatment of tuberculosis that is currently undergoing human trials. Like its progenitors metronidazole and CGI-17341, PA-824 is a prodrug of the nitroimidazole class, requiring bioreductive activation of an aromatic nitro group to exert an antitubercular effect. We have confirmed that resistance to PA-824 (a nitroimidazo-oxazine) and CGI-17341 (a nitroimidazo-oxazole) is most commonly mediated by loss of a specific glucose-6-phosphate dehydrogenase (FGD1) or its deazaflavin cofactor F 420, which together provide electrons for the reductive activation of this class of molecules. Although FGD1 and F 420 are necessary for sensitivity to these compounds, they are not sufficient and require additional accessory proteins that directly interact with the nitroimidazole. To understand more proximal events in the reductive activation of PA-824, we examined mutants that were wild-type for both FGD1 and F 420 and found that, although these mutants had acquired high-level resistance to PA-824 (and another nitroimidazo-oxazine), they retained sensitivity to CGI-17341 (and a related nitroimidazo-oxazole). Microarray-based comparative genome sequencing of these mutants identified lesions in Rv3547, a conserved hypothetical protein with no known function. Complementation with intact Rv3547 fully restored sensitivity to nitroimidazo-oxazines and restored the ability of Mtb to metabolize PA-824. These results suggest that the sensitivity of Mtb to PA-824 and related compounds is mediated by a protein that is highly specific for subtle structural variations in these bicyclic nitroimidazoles.comparative genome sequencing ͉ F420 ͉ nitroimidazole

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Structures of coenzyme F 420 in Mycobacterium species

Cited by 51 publications

References 20 publications

Crystal Structures of F420-dependent Glucose-6-phosphate Dehydrogenase FGD1 Involved in the Activation of the Anti-tuberculosis Drug Candidate PA-824 Reveal the Basis of Coenzyme and Substrate Binding

Crystal Structures of F420-dependent Glucose-6-phosphate Dehydrogenase FGD1 Involved in the Activation of the Anti-tuberculosis Drug Candidate PA-824 Reveal the Basis of Coenzyme and Substrate Binding

Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis

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Structures of coenzyme F 420 in Mycobacterium species

Cited by 51 publications

References 20 publications

Crystal Structures of F420-dependent Glucose-6-phosphate Dehydrogenase FGD1 Involved in the Activation of the Anti-tuberculosis Drug Candidate PA-824 Reveal the Basis of Coenzyme and Substrate Binding

Crystal Structures of F420-dependent Glucose-6-phosphate Dehydrogenase FGD1 Involved in the Activation of the Anti-tuberculosis Drug Candidate PA-824 Reveal the Basis of Coenzyme and Substrate Binding

Physiology, Biochemistry, and Applications of F420- and Fo-Dependent Redox Reactions

Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis

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Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions