Pyrazinamidase/nicotinamidase (PncA) (PncA)

Pyrazinamidase/nicotinamidase (PncA) is a critical bacterial enzyme, primarily characterized in Mycobacterium tuberculosis, that functions as a nicotinamidase within the NAD+ salvage pathway by converting nicotinamide to nicotinic acid (UniProt P9WNY5). Beyond its metabolic role, PncA is the essential activator of the first-line antitubercular prodrug pyrazinamide (PZA), catalyzing its conversion into the active form, pyrazinoic acid (POA) (Scorpio & Zhang, 1996). The active POA moiety disrupts the bacterial membrane potential and inhibits multiple targets, including RpsA and PanD, which is particularly effective against non-replicating persisters in acidic environments (Zhang et al., 2014). Mutations across the pncA gene are the most common cause of clinical resistance to pyrazinamide, making it a vital biomarker for molecular drug susceptibility testing (Jureen et al., 2008). Notably, Mycobacterium bovis exhibits innate resistance to PZA due to a characteristic H57D mutation in the pncA gene (Scorpio et al., 1997). The enzyme's activity is dependent on metal ions, typically iron or manganese, which are coordinated at the active site to facilitate the hydrolytic reaction (FEBS J, 2008).

Other names

PyrazinamidaseNicotinamidasePZaseNicotinamide amidohydrolasepncA

Enzymatic activation of the prodrug pyrazinamide into its active bactericidal form, pyrazinoic acid, which subsequently disrupts bacterial membrane potential and cellular energetics.