Selengut, J. D., Haft, D. H.
Unexpected Abundance of Coenzyme F420-dependent Enzymes In the Genomes of Mycobacterium tuberculosis and Other Actinobacteria
J Bacteriol. 2010 Jul 30;
Regimens targetting Mycobacterium tuberculosis, the causative agent of tuberculosis disease, require long courses of treatment and a combination of three or more drugs. An increase in drug resistant strains of M. tuberculosis demonstrates the need for additional TB-specific drugs. A notable feature of M. tuberculosis is coenzyme F420, which is distributed sporadically and sparsely among prokaryotes. This distribution allowed for comparative genomics-based investigations. Phylogenetic profiling (comparison of differential gene content) based on F420 biosynthesis nominated many Actinobacterial proteins as candidate F420-dependent enzymes. Three such families dominated the results: the luciferase-like monooxygenase (LLM), pyridoxamine 5'-phosphate oxidase (PPOX), and the deazaflavin-dependent nitroreductase (DDN) families. The DDN family was determined to be limited to F420-producing species. The LLM and PPOX families were observed in F420-producing species as well as species lacking F420 but were particularly numerous in many Actinobacterial species including M. tuberculosis. Partitioning the LLM and PPOX families based on an organism's ability to make F420 allowed the application of the SIMBAL profiling method to identify F420-correlated subsequences. These regions were found to correspond to flavinoid cofactor binding sites. Significantly, these results showed that M. tuberculosis encodes at least 28 separate F420-dependent enzymes, most of unknown function, and a paucity of FMN-dependent proteins in these families. While prevalent in Mycobacteria, markers of F420 biosynthesis appeared to be absent from normal human gut flora. These findings suggested that M. tuberculosis relies heavily on coenzyme F420 for its redox reactions. This dependence, and the cofactor's rarity may make F420-related proteins promising drug targets.