Pyrazinamidase and fatty acid synthase I pathway (PncA/FAS-I)

The Mycobacterium tuberculosis pyrazinamidase (PncA) activation pathway is a critical mechanism for the efficacy of the first-line antitubercular drug pyrazinamide (PZA). PZA is a prodrug that requires conversion into its active moiety, pyrazinoic acid (POA), by the bacterial enzyme pyrazinamidase (Zhang et al., 2003). Once activated, POA exerts its bactericidal effects by targeting multiple cellular processes, most notably the inhibition of Fatty Acid Synthase I (FAS-I) (Zimhony et al., 2000). FAS-I is a large, multifunctional enzyme complex essential for the synthesis of C16 to C26 fatty acids, which are vital precursors for the production of mycolic acids in the mycobacterial cell wall (Zimhony et al., 2000; BenchChem, 2025). Additionally, POA has been shown to inhibit the ribosomal protein S1 (RpsA), affecting trans-translation, and the aspartate decarboxylase (PanD), which is involved in coenzyme A biosynthesis (NIH, 2015; NIH, 2024). By disrupting fatty acid synthesis and other downstream processes, this pathway plays a unique role in killing semi-dormant bacilli within acidic environments, thereby shortening the duration of tuberculosis treatment (NIH, 2024).

Other names

Mycobacterium tuberculosis pyrazinamidase activation pathway and downstream fatty acid synthase I-related processesPncAPyrazinamidaseFAS-IFatty acid synthase IPZA activation pathwayNicotinamidase

Pyrazinamide is a prodrug that enters Mycobacterium tuberculosis via passive diffusion and is converted by the mycobacterial enzyme pyrazinamidase (PncA) into its active form, pyrazinoic acid (POA) (Zhang et al., 2003). POA then inhibits Fatty Acid Synthase I (FAS-I), disrupting the synthesis of short-chain fatty acids (C16-C26) which are essential precursors for mycolic acids in the cell wall (Zimhony et al., 2000). POA also acts as a protonophore to disrupt membrane potential and inhibits other targets like RpsA and PanD (NIH, 2015; NIH, 2024).