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

Elie Rafidinarivo²^,*^,, Marie-Antoinette Lanéelle^*^,, Henri Montrozier^*^,, Pedro Valero-Guillén, José Astola^**, Marina Luquin^**, Jean-Claude Promé^*^, and Mamadou Daffé¹^,*^,

^* Université Paul Sabatier (Toulouse III), Institut de Pharmacologie et Biologie Structurale (IPBS), 205 route de Narbonne, 31077 Toulouse Cedex, France
Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5089), IPBS, Department ‘Mécanismes Moléculaires des Infections Mycobactériennes,’ 205 route de Narbonne, 31077 Toulouse Cedex, France
Departamento de Genética y Microbiologia, Facultad de Medicina y Odontologia, Universidad de Murcia, 30100 Murcia, Spain
^** Departament de Genètica y Microbiologia, Facultat de Ciences, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain
^² Present address of E. Rafidinarivo: Ecole Normale Niveau III, B.P. 881, 101 Antananarivo, Madagascar.

The NMR equipment was funded via European structural funds,CNRS, and the Région Midi-Pyrénées fundsas part of the 2000–2006 CPER program.

Published, JLR Papers in Press, September 4, 2008.

^¹ To whom correspondence should be addressed. e-mail: mamadou.daffe{at}ipbs.fr

Mycolic acids, the hallmark of mycobacteria and related bacteria,are major and specific components of their cell envelope andessential for the mycobacterial survival. Mycobacteria containstructurally related long-chain lipids, but the metabolic relationshipsbetween these various classes of compounds remain obscure. Toaddress this question a series of C₃₅ to C₅₄ nonhydroxylatedfatty acids (mycobacteric acids), ketones, and alcohols structurallyrelated to the C_70–80 dicyclopropanated or diethylenicmycolic acids were characterized in three mycobacterial strainsand their structures compared. The relationships between theselong-chain acids and mycolic acids were established by followingthe in vivo traffic of ¹⁴C labeled ${alpha}$ -mycolic acids purified fromthe same mycobacterial species. The labeling was exclusivelyfound in mycobacteric acids. The mechanism of this degradationwas established by incorporation of ¹⁸O₂ into long-chain lipidsand shown to consist in the rupture of mycolic acids betweencarbon 3 and 4 by a Baeyer-Villiger-like reaction. We also demonstratedthat mycobacteric acids occur exclusively in the triacylglycerol(TAG) fraction where one molecule of these acids esterifiesone of the three hydroxyl groups of glycerol. Altogether, thesedata suggest that these compounds represent a pathway of metabolicenergy that would be used by mycobacteria in particular circumstances.

Supplementary key words mycobacteria • biosynthesis • catabolism • Baeyer-Villiger reaction • oxidation

Abbreviations: amu, atomic mass unit; BVMO, Baeyer-Villiger monooxygenases; EI, electron impact; MALDI-TOF, MALDI-time-of-flight; MS, mass spectrometry; TAG, triacylglycerol

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