Mycolic acid biosynthetic pathway (FAS-II) (FAS-II)

The mycolic acid biosynthetic pathway is a critical metabolic process in mycobacteria, responsible for producing the long-chain fatty acids that constitute the major component of the protective cell envelope (Marrakchi et al., 2014). This pathway involves two distinct systems: Fatty Acid Synthase I (FAS-I), which produces short-chain fatty acids, and Fatty Acid Synthase II (FAS-II), which elongates them into mycolic acids (Bhatt et al., 2007). These lipids form a thick, waxy layer that acts as a permeability barrier against many antibiotics and host immune defenses, making it essential for the survival and virulence of Mycobacterium tuberculosis (Nataraj et al., 2015). Several major anti-tubercular drugs, such as Isoniazid and Ethionamide, specifically target this pathway by inhibiting the enoyl-ACP reductase enzyme, InhA (Vilchèze & Jacobs, 2007). Disruption of this process leads to the loss of acid-fastness and eventual lysis of the bacterial cell. Because the FAS-II system is absent in humans, it represents a highly selective target for drug development. However, resistance mediated by mutations in activating enzymes (like KatG) or the target itself (InhA) remains a significant clinical challenge (Unissa et al., 2016). Newer agents like Delamanid and Pretomanid also interfere with mycolic acid synthesis, though through different mechanisms involving nitroreductase activation (Stover et al., 2000). Overall, this metabolic network is fundamental to mycobacterial physiology and remains a cornerstone of tuberculosis chemotherapy.

Other names

Mycobacterial cell envelope metabolismMycolic acid synthesisFatty acid synthase II systemMycobacterial cell envelope/mycolic-acid-dependent metabolism

Inhibition of key enzymes within the Fatty Acid Synthase II (FAS-II) system, such as enoyl-ACP reductase (InhA), which prevents the elongation of fatty acids into long-chain mycolic acids required for the mycobacterial cell wall.