Pyrazinamidase (PncA) (PncA)

Pyrazinamidase (PncA) is an essential enzyme in Mycobacterium tuberculosis responsible for the conversion of the prodrug pyrazinamide into its active form, pyrazinoic acid (POA) (UniProt P9WNX3). This activation is a critical step in the treatment of tuberculosis, as POA exerts potent bactericidal effects, particularly against semi-dormant bacilli in acidic environments (StatPearls, Pyrazinamide). Once formed, POA targets multiple cellular processes, including the inhibition of trans-translation via ribosomal protein S1 (RpsA) and the disruption of pantothenate biosynthesis through the inhibition of aspartate 1-decarboxylase (PanD) (PubMed: 21852440, 24613914). Additionally, POA is thought to collapse the bacterial membrane potential and interfere with energy metabolism (PubMed: 12874041). Mutations in the pncA gene are the primary mechanism of clinical resistance to pyrazinamide, occurring in the majority of resistant isolates (PubMed: 28807625). Understanding the PncA-mediated activation pathway is vital for optimizing multidrug-resistant tuberculosis (MDR-TB) therapy and developing new diagnostic tools.

Other names

NicotinamidasePyrazinamide amidohydrolasePZAaseNicotinamide amidohydrolase

Pyrazinamidase acts as a prodrug-activating enzyme that converts the antitubercular drug pyrazinamide into its active form, pyrazinoic acid (POA). Once activated, POA accumulates within the Mycobacterium tuberculosis cell, where it disrupts the membrane potential and inhibits downstream targets such as ribosomal protein S1 (RpsA), which is involved in trans-translation, and aspartate 1-decarboxylase (PanD), which is essential for pantothenate (Vitamin B5) biosynthesis (PubMed: 21852440, 24613914).