How mycobacteria initiate mycolic acid biosynthesis in the fatty acid synthase II system?

SAVORETTI, F; CROTTA ASIS, A; GRAMAJO, H; GAGO, G.

Congreso; X Meeting of the Latin American Society of Tuberculosis and other Mycobacteriosis; 2021

SLAM-TB

The biosynthesis of fatty acids in mycobacteria involves two different systems of fatty acid synthases (FAS), FAS I and FAS II. Both synthases are involved in the biosynthesis of membrane fatty acids and several lipid components of the cell wall. For example, for the biosynthesis of mycolic acid, essential for viability and pathogenesis, FAS I and FAS II have to work in a coordinate way to maintain lipid homeostasis. These two systems are linked by a beta-ketoacyl-acyl carrier protein synthase III, named FabH, that catalyzes the first reaction of FAS-II using FAS-I products as substrate. Although Mycobacterium tuberculosis FabH has been studied at the biochemical level, there are no genetic analysis that unequivocally establishes the physiological role of this enzyme. In this work, we constructed a mutant strain in the putative gene coding for FabH in Mycobacterium smegmatis and carried out a physiological characterization and lipid analysis. Our results show that the fabH gene it is not essential in the studied conditions and the resulting mutant strain is able to synthesize mycolic acids (the final product of the FAS-II pathway). However, we observed different growth behavior under different stress conditions, including altered response to isoniazid. We believe there must be other gene/s, distantly related to well-known beta-ketoacyl-acyl carrier protein synthases III, implicated in mycolic acid biosynthesis in M smegmatis. The characterization of key enzymes participating in mycolic acid biosynthesis not only allows better understanding of their role in the physiology of mycobacteria, but also might lead to the identification of new drug targets for the development of new antimycobacterial compounds.