Mycolic acid biosynthesis pathway enzymes (FAS-II)

The mycolic acid biosynthesis pathway in Mycobacterium tuberculosis is a critical metabolic route responsible for producing the unique, long-chain fatty acids (C60-C90) that form the protective waxy envelope of the bacterium [1.4.1, 1.4.2]. This pathway is essential for mycobacterial viability, virulence, and resistance to environmental stress and antibiotics [1.3.3, 1.4.1]. It involves two coordinated systems: Fatty Acid Synthase I (FAS-I), which synthesizes short-chain precursors, and the Fatty Acid Synthase II (FAS-II) system, which elongates these into meromycolate chains through a cycle of enzymes including InhA, KasA, KasB, MabA, and the HadABC complex [1.2.1, 1.3.2]. Final processing steps involve the condensation of these chains by Pks13 and their transport across the plasma membrane by MmpL3 [1.1.2, 1.1.3]. This pathway is the primary target for several cornerstone antitubercular drugs; for instance, isoniazid and ethionamide are prodrugs that, once activated, inhibit the enoyl-ACP reductase InhA [1.1.1, 1.5.3]. Other inhibitors like delamanid and pretomanid also disrupt mycolic acid synthesis, while experimental compounds target KasA or MmpL3 to overcome existing drug resistance [1.5.1, 1.5.4]. Disruption of these enzymes leads to the loss of cell wall integrity, making the pathway one of the most validated and exploited areas for tuberculosis drug discovery [1.3.2, 1.4.1].

Other names

Fatty acid synthase II systemMycolic acid biosynthetic pathwayMeromycolate synthesis pathwayFAS-II systemMycobacterial cell wall synthesis pathway

Inhibition of key enzymes in the FAS-II elongation cycle (e.g., InhA, KasA/B, HadABC) or the final assembly and transport machinery (e.g., Pks13, MmpL3), resulting in the depletion of mycolic acids and subsequent mycobacterial cell wall collapse.