TY - JOUR T1 - Unexpected abundance of coenzyme F(420)-dependent enzymes in Mycobacterium tuberculosis and other actinobacteria JF - Journal of bacteriologyJournal of bacteriology Y1 - 2010 A1 - J. Selengut A1 - Haft, Daniel H. KW - Actinobacteria KW - Amino Acid Sequence KW - Binding Sites KW - Coenzymes KW - Flavonoids KW - Gene Expression Profiling KW - Gene Expression Regulation, Bacterial KW - Genome, Bacterial KW - molecular biology KW - Molecular Sequence Data KW - Molecular Structure KW - Mycobacterium tuberculosis KW - Phylogeny KW - Protein Conformation KW - Riboflavin AB - 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. VL - 192 N1 - http://www.ncbi.nlm.nih.gov/pubmed/20675471?dopt=Abstract ER -