F420-dependent deazaflavin nitroreductase (Ddn)

F420-dependent deazaflavin nitroreductase, commonly known as Ddn, is a specialized bacterial enzyme primarily characterized in Mycobacterium tuberculosis (Manjunatha et al., 2006, PNAS; UniProt P9WPG3). It serves as the essential activator for the nitroimidazole class of antitubercular prodrugs, including pretomanid and delamanid (Singh et al., 2008, Science). The enzyme utilizes the deazaflavin cofactor F420 to catalyze the reduction of the nitro group on these compounds, a process that releases reactive nitrogen species such as nitric oxide (Cellitti et al., 2012, Protein Science). These reactive intermediates exert a dual lethal effect by inhibiting mycolic acid biosynthesis, which is crucial for cell wall integrity, and by inducing respiratory poisoning in anaerobic, non-replicating bacteria (Singh et al., 2008, Science). Because Ddn is the sole enzyme responsible for this activation, it is a critical determinant of drug susceptibility (Manjunatha et al., 2006, PNAS). Mutations in the ddn gene or defects in the F420 biosynthetic and recycling pathways are the primary drivers of clinical resistance to nitroimidazole therapy (Cellitti et al., 2012, Protein Science; UniProt P9WPG3). Consequently, Ddn is a major focus for diagnostic monitoring and the development of improved regimens for multi-drug resistant tuberculosis (Manjunatha et al., 2006, PNAS).

Other names

Deazaflavin-dependent nitroreductaseRv3547Ddn enzyme

Reductive activation of nitroimidazole prodrugs to generate reactive nitrogen species (e.g., nitric oxide) that inhibit mycolic acid synthesis and bacterial respiration.