Mycobacterium tuberculosis deazaflavin-dependent nitroreductase (Ddn) (Ddn)

Mycobacterium tuberculosis deazaflavin-dependent nitroreductase (Ddn) is a specialized enzyme that plays a critical role in the metabolism of nitro-compounds within the pathogen (UniProt P9WPG3). It specifically utilizes the reduced form of the deazaflavin cofactor F420 (F420H2) to catalyze the reduction of its substrates (Manjunatha et al., 2006). While its endogenous biological function involves the detoxification of reactive carbonyl species, it is most notable in clinical medicine as the primary activator for the bicyclic nitroimidazole class of antitubercular drugs, including pretomanid and delamanid (Singh et al., 2008). Upon binding these prodrugs, Ddn facilitates their reduction, leading to the release of reactive nitrogen species such as nitric oxide (Cell Chemical Biology, 2020). These reactive intermediates subsequently inhibit mycolic acid synthesis and disrupt bacterial respiration, effectively killing both replicating and non-replicating bacilli (PubMed: 19039335). Consequently, mutations in the ddn gene or the associated F420 biosynthetic pathway are the leading mechanisms of clinical resistance to these essential components of multidrug-resistant tuberculosis (MDR-TB) treatment regimens (DrugBank DB11638).

Other names

Rv3547Deazaflavin-dependent nitroreductaseF420-dependent nitroreductaseNitroreductase Ddn

Reductive activation of bicyclic nitroimidazole prodrugs into reactive nitrogen species