Unexpected abundance of coenzyme F420-dependent enzymes in Mycobacterium tuberculosis and other actinobacteria

Regimens targeting Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), 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 [F.sub.420], which is distributed sporadically and sparsely among prokaryotes. This distribution allows for comparative genomics-based investigations. Phylogenetic profiling (comparison of differential gene content) based on [F.sub.420] biosynthesis nominated many actinobacterial proteins as candidate [F.sub.420]-dependent enzymes. Three such families dominated the results: the luciferase-like monooxygenase (LLM), pyridoxamine 5'-phosphate oxidase (PPOX), and deazaflavin-dependent nitroreductase (DDN) families. The DDN family was determined to be limited to [F.sub.420]-producing species. The LLM and PPOX families were observed in [F.sub.420]-producing species as well as species lacking [F.sub.420] 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 [F.sub.420] allowed the application of the SIMBAL (sites inferred by metabolic background assertion labeling) profiling method to identify [F.sub.420]-correlated subsequences. These regions were found to correspond to flavonoid cofactor binding sites. Significantly, these results showed that M. tuberculosis carries at least 28 separate [F.sub.420]-dependent enzymes, most of unknown function, and a paucity of flavin mononucleotide (FMN)-dependent proteins in these families. While prevalent in mycobacteria, markers of [F.sub.420] biosynthesis appeared to be absent from the normal human gut flora. These findings suggest that M. tuberculosis relies heavily on coenzyme [F.sub.420] for its redox reactions. This dependence and the cofactor's rarity may make [F.sub.420]-related proteins promising drug targets. doi: 10.1128/JB.00425-10