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(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(420) biosynthesis nominated many actinobacterial
proteins as candidate F(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(420)-producing species. The LLM and PPOX families were observed in F(420)-producing species as well as species lacking
F(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(420) allowed the application of the SIMBAL (sites inferred by metabolic background assertion labeling) profiling method to identify F(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(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(420) biosynthesis appeared to be absent from the normal human gut flora. These findings suggest that M.
tuberculosis relies heavily on
coenzyme F(420) for its redox reactions. This dependence and the cofactor's rarity may make F(420)-related
proteins promising
drug targets.