4 A Comprehensive Overview of Mycolic Acid Structure and Biosynthesis

This chapter focuses on the major metabolic steps and essential enzymatic players in the mycolic acid biosynthetic pathway, providing a historical perspective and highlighting the key advances of the last few years in this dynamic area. Information relative to the mycolic acid structure has been brought through the application of early and modern chemical techniques, in particular thin-layer chromatography (TLC), gas chromatography (GC), high-pressure liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy. The structures of mycolic acids of genera other than mycobacteria were found to be relatively simple in terms of chemical functions, being composed only of homologous series with various numbers of double bonds, up to 7 for some Gordona species. The pathway for synthesis of mycolic acids could be virtually divided into three major steps: (1) the synthesis and elongation of fatty acids to give precursors of both the α-branch and the very long meromycolic chain; (2) the elongation and introduction of functional modifications on the meromycolic chain; and (3) the condensation of two long-chain fatty acids, followed by a reduction to yield the mycolic acid specific motif. More recently, the involvement of the AccD4 carboxyltransferase in mycolic acid synthesis and its essentiality for mycobacterial survival have been demonstrated. Fatty acid synthase (FAS)-II has been shown to elongate medium-chain-length C12 to C16 fatty acids to yield C18-C30 acyl-ACPs in vitro, which are most likely the precursors of the very long-chain meromycolic acids.