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This Week in TB R&D- 3 August 2010


3 Aug 2010
by Working Group

Cofactor F420 Structure

The need for the identification of novel TB drug targets and biomarkers has been highlighted in a few of our posts over the last several months. A recent epublication (online manuscript before print) in the Journal of Bacteriology by Jeremy D. Selengut and Daniel H. Haft highlights the use of comparative genomic profiling tools to identify putative novel drug targets among known and previously unpredicted coenzyme F420-dependent enzymes.

Coenzyme F420 is a deazaflavin analog of flavin mononucleotide (FMN), a phosphorylated form of riboflavin. Coenzyme F420 is involved in cellular redox reactions and is predicted to play a role in mycobacterial survival. Interestingly, this enzyme cofactor has been reported to be essential in PA-824 metabolism and the drug’s anti-tubercular effects on non-replicating M. tb.

Phylogenetic profiling yielded three families F420-dependent enzymes: the luciferase-like monooxygenase (LLM), pyridoxamine 5’-phosphate oxidase (PPOX), and deazaflavin-dependent nitroreductase (DDN) families. Further genetic analysis of the LLM and PPOX enzyme families using SIMBAL, Sites Inferred from Metabolic background Labeling, not only identified putative F420-dependent enzyme members, results also predicted probable cofactor verses substrate sequence binding regions in some of these enzymes and differences between F420 binding and FMN binding.

Of important note, results also revealed a divergence of the abundance and type of flavinoid-dependent enzymes present in M. smeg and M. tb. This may be a critical observation for future studies to understand host:pathogen survival mechanisms by determining which flavinoid-dependent enzymes are essential.

How might these combinatorial genomic approaches be used to identify M. tb diagnostic and/or prognostic biomarker? If coenzyme F420 is highly fluorescent under UV light, might this be a tool to further understand the role of coenzyme F420 in M. tb macrophage pathogenesis? What are your thoughts and comments? Please share them below.

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