Meromycolate methyltransferase (MmaA family) (MmaA enzymes)

Methoxy- and keto-mycolic acid synthesis enzymes, primarily comprising the MmaA (meromycolate methyltransferase) family and CmaA2, are essential for the biosynthesis of oxygenated mycolic acids in Mycobacterium tuberculosis (Yuan et al., 1998). These enzymes catalyze the modification of the meromycolate chain, introducing critical functional groups such as methoxy and keto moieties, as well as cyclopropyl rings, which are vital for the structural integrity and low permeability of the mycobacterial cell wall (Bhowruth et al., 2012). MmaA4 (also known as Hma) is a central enzyme in this pathway, introducing a hydroxyl group that serves as the common precursor for both methoxy- and keto-mycolates (Cantrell et al., 2004). The presence of these oxygenated mycolates is closely linked to the pathogen's virulence, its ability to survive within host macrophages, and its resistance to host immune responses. Drugs such as thiacetazone and isoxyl target these enzymes—specifically MmaA4 and MmaA2—after being activated by the bacterial monooxygenase EthA, thereby disrupting cell wall assembly and inhibiting bacterial growth (Boissier et al., 2006).

Other names

Methoxy- and keto-mycolic acid synthesis enzymesMmaA familyOxygenated mycolic acid synthasesHmaHydroxymycolate synthaseMeromycolate methyltransferases

Inhibition of the MmaA family of SAM-dependent methyltransferases, particularly MmaA4 (Hma) and MmaA2, which prevents the introduction of methoxy and keto groups into the meromycolate chain, leading to cell wall instability (Boissier et al., 2006; Bhowruth et al., 2012).