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J. Biol. Chem., Vol. 278, Issue 38, 36285-36295, September 19, 2003

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Identification of the Required Acyltransferase Step in the Biosynthesis of the Phosphatidylinositol Mannosides of Mycobacterium Species^*

Jana Korduláková   ¶, Martine Gilleron ||, Germain Puzo ||, Patrick J. Brennan **, Brigitte Gicquel , Katarína Mikuová  and Mary Jackson  

From the Unité de Génétique Mycobactérienne, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France, the ^||Institut de Pharmacologie et de Biologie Structurale du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex, France, the Department of Biochemistry, Comenius University in Bratislava, Faculty of Natural Sciences, Mlynska dolina CH-1, 84215 Bratislava, Slovak Republic, and the ^**Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523

Fatty acyl functions of the glycosylated phosphatidylinositol (GPI) anchors of the phosphatidylinositol mannosides (PIM), lipomannan (LM), and lipoarabinomannan (LAM) of mycobacteria play a critical role in both the physical properties and biological activities of these molecules. In a search for the acyltransferases that acylate the GPI anchors of PIM, LM, and LAM, we examined the function of the mycobacterial Rv2611c gene that encodes a putative acyltransferase involved in the early steps of phosphatidylinositol mannoside synthesis. A Rv2611c mutant of Mycobacterium smegmatis was constructed which exhibited severe growth defects and contained an increased amount of phosphatidylinositol mono- and di-mannosides and a decreased amount of acylated phosphatidylinositol di-mannosides compared with the wild-type parental strain. In cell-free assays, extracts from M. smegmatis overexpressing the M. tuberculosis Rv2611c gene incorporated [¹⁴C]palmitate into acylated phosphatidylinositol mono- and di-mannosides, and transferred cold endogenous fatty acids onto ¹⁴C-labeled phosphatidylinositol mono- and di-mannosides more efficiently than extracts from the wild-type strain. Cell-free extracts from the Rv2611c mutant of M. smegmatis were greatly impaired in these respects. This work provides evidence that Rv2611c is the acyltransferase that catalyzes the acylation of the 6-position of the mannose residue linked to position 2 of myo-inositol in phosphatidylinositol mono- and di-mannosides, with the mono-mannosylated lipid acceptor being the primary substrate of the enzyme. We also provide the first evidence that two distinct pathways lead to the formation of acylated PIM₂ from PIM₁ in mycobacteria.

Received for publication, April 8, 2003 , and in revised form, July 7, 2003.

^* This work was supported in part by the Slovak Republic/USA Joint Research Grant 032/2001 from APVT Slovakia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Recipient of a Marie Curie Fellowship (CT-2000-00058) from the European Economic Community.

To whom correspondence should be addressed. Tel.: 33-1-45-68-88-77; Fax: 33-1-45-68-88-43; E-mail: mjackson{at}pasteur.fr.

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