Fatty acid synthase I (FAS-I) (FAS-I)

Fatty acid synthase I (FAS-I) is a multi-functional enzyme complex in Mycobacterium tuberculosis that plays a pivotal role in the de novo synthesis of fatty acids (Zimhony et al., 2000). It produces short-chain fatty acids (C16-C26) that are subsequently elongated by the FAS-II system to form mycolic acids, which are essential components of the mycobacterial cell wall (UniProt P9WGR1). Pyrazinoic acid (POA), the active metabolite of the prodrug pyrazinamide (PZA), has been shown to inhibit FAS-I, thereby disrupting the production of these critical lipid precursors (Zimhony et al., 2000). This inhibition is particularly effective in the acidic environments of host macrophages, where POA accumulates and exerts its bactericidal effects against semi-dormant bacilli (Zhang et al., 2014). Although other targets such as ribosomal protein S1 (RpsA) and aspartate decarboxylase (PanD) have been identified, FAS-I remains a key enzyme involved in the metabolic disruption caused by pyrazinoic acid (Shi et al., 2014). Understanding the interaction between POA and FAS-I is crucial for addressing drug resistance in tuberculosis treatment.

Other names

FAS1Fatty acid synthaseMultienzyme complex FAS-IMtb FAS-IFatty acid synthetase

Pyrazinoic acid (POA) acts as a competitive inhibitor of the fatty acid synthase I (FAS-I) enzyme complex in Mycobacterium tuberculosis. Upon conversion from the prodrug pyrazinamide by the bacterial enzyme pyrazinamidase (PncA), POA binds to the FAS-I complex, specifically interfering with the synthesis of C16 to C26 fatty acids (Zimhony et al., 2000). This blockade prevents the downstream synthesis of mycolic acids, leading to cell wall instability and bacterial death, particularly in non-replicating or slowly growing populations (Zhang & Mitchison, 2003).