Trafficking pathways of mycolic acids: structures, origin, mechanism of formation, and storage form of mycobacteric acids

Abstract

Mycolic acids, the hallmark of mycobacteria and related bacteria, are major and specific components of their cell envelope and essential for the mycobacterial survival. Mycobacteria contain structurally related long-chain lipids, but the metabolic relationships between these various classes of compounds remain obscure. To address this question a series of C 35 to C 54 nonhydroxylated fatty acids (mycobacteric acids), ketones, and alcohols structurally related to the C 70-80 dicyclopropanated or diethylenic mycolic acids were characterized in three mycobacterial strains and their structures compared. The relationships between these longchain acids and mycolic acids were established by following the in vivo traffic of 14 C labeled a-mycolic acids purified from the same mycobacterial species. The labeling was exclusively found in mycobacteric acids. The mechanism of this degradation was established by incorporation of 18 O 2 into long-chain lipids and shown to consist in the rupture of mycolic acids between carbon 3 and 4 by a BaeyerVilliger-like reaction. We also demonstrated that mycobacteric acids occur exclusively in the triacylglycerol (TAG) fraction where one molecule of these acids esterifies one of the three hydroxyl groups of glycerol. Altogether, these data suggest that these compounds represent a pathway of metabolic energy that would be used by mycobacteria in particular circumstances. Mycolic acids, 2-alkyl-branched, 3-hydroxylated longchain fatty acids, represent major (up to 40% of cell wall dry mass) and specific constituents of the envelope of members of the genus Mycobacterium (M.) that includes several pathogens such as M. tuberculosis and M. leprae, the causative agents of tuberculosis and leprosy, respectively. These fatty acids play a crucial structural role in the envelope architecture (1-4) and are essential for the mycobacterial growth (5-7). Mycolic acids covalently linked to the cell wall arabinogalactan are organized with other lipids to form an outer barrier with an extremely low fluidity that confers an exceptional low permeability to mycobacteria (8). Trehalose mycolates, found noncovalently attached to the cell wall core, are known to be important for the physiology and virulence of M. tuberculosis (3). In addition, the biosynthesis of mycolic acids is the target of several antituberculous drugs, notably isoniazid (2,3,9).Mycolic acids are found in mycobacterial species as a mixture of structurally related molecules that differ from one another by the nature of the chemical groups at the socalled "proximal" and "distal" positions (relative to the carboxyl group) of their main "meromycolic" chain (Fig. 1). The least polar a-mycolates is ubiquitous in mycobacteria and consist of C 74-82 fatty acids that contain two cis cyclopropyl groups or cis/trans double bonds at the proximal and distal positions (Fig. 1); shorter apolar structural analogs (C 60-68 ), called a′-mycolates, may occur in someThe NMR equipment was funded via European structural funds, CNRS, and the Région Midi-...

Metabolite analysis of Mycobacterium species under aerobic and hypoxic conditions reveals common metabolic traits

“…The MALDI data suggested that TAG was the main compound of the secretion as no other spectra were detected in the sample. The two series of peaks in the TAG spectrum of M. smegmatis further indicated two different types of TAGs due to a combination of fatty and mycolic acids with different chain lengths as described for M. brumae (Rafidinarivo et al, 2009).…”

“…5b). The fingerprint of the molecular ion peaks was typical for MALDI spectra of TAG as seen through comparison with TAG spectra of M. brumae (Rafidinarivo et al, 2009). The MALDI data suggested that TAG was the main compound of the secretion as no other spectra were detected in the sample.…”

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