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J. Biol. Chem., Vol. 283, Issue 3, 1419-1427, January 18, 2008

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Investigating the Function of the Putative Mycolic Acid Methyltransferase UmaA

DIVERGENCE BETWEEN THE MYCOBACTERIUM SMEGMATIS AND MYCOBACTERIUM TUBERCULOSIS PROTEINS^*

Françoise Laval, Ruth Haites^¶, Farahnaz Movahedzadeh^||1, Anne Lemassu, Chinn Yi Wong^¶, Neil Stoker^||, Helen Billman-Jacobe^¶2, and Mamadou Daffé²³

From the Institut de Pharmacologie et Biologie Structurale (IPBS), Université Paul Sabatier (Toulouse III), 205 route de Narbonne, 31077 Toulouse Cedex, France, the Department Mécanismes Moléculaires des Infections Mycobactériennes, Institut de Pharmacologie et Biologie Structurale (IPBS), Centre National de la Recherche Scientifique (Unité Mixte de Recherche 5089), 205 route de Narbonne, 31077 Toulouse Cedex, France, the ^¶Department of Microbiology and Immunology, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia, and the ^||Department of Pathology and Infectious Diseases, Royal Veterinary College, Royal College Street, London NW1 0TU, United Kingdom

Mycolic acids are major and specific lipid components of the cell envelope of mycobacteria that include the causative agents of tuberculosis and leprosy, Mycobacterium tuberculosis and Mycobacterium leprae, respectively. Subtle structural variations that are known to be crucial for both their virulence and the permeability of their cell envelope occur in mycolic acids. Among these are the introduction of cyclopropyl groups and methyl branches by mycolic acid S-adenosylmethionine-dependent methyltransferases (MA-MTs). While the functions of seven of the M. tuberculosis MA-MTs have been either established or strongly presumed nothing is known of the roles of the remaining umaA gene product and those of M. smegmatis MA-MTs. Mutants of the M. tuberculosis umaA gene and its putative M. smegmatis orthologue, MSMEG0913, were created. The lipid extracts of the resulting mutants were analyzed in detail using a combination of analytical techniques such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and proton nuclear magnetic resonance spectroscopy, and chemical degradation methods. The M. smegmatis mutants no longer synthesized subtypes of mycolates containing a methyl branch adjacent to either trans cyclopropyl group or trans double bond at the "proximal" position of both - and epoxy-mycolates. Complementation with MSMEG0913, but not with umaA, fully restored the wild-type phenotype in M. smegmatis. Consistently, no modification was observed in the structures of mycolic acids produced by the M. tuberculosis umaA mutant. These data proved that despite their synteny and high similarity umaA and MSMEG0913 are not functionally orthologous.

Received for publication, October 26, 2007

^* The work was supported by the CNRS (France), the Australian National Health and Medical Research Council Project Grant 400025 (to H. B. J.), the Wellcome Trust (Project Grant 051880), and the European Union TB Vaccine Cluster Contract No. QLK2-1999-01093, and Wellcome Trust Grant 073237 (to N. S.). The Nuclear Magnetic Resonance spectrometers were financed by the CNRS (France), the University Paul Sabatier (Toulouse), the "Région Midi-Pyrénées," and the European Structural Funds (FEDER). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ Present address: Inst. for Tuberculosis Research College of Pharmacy, Rm 412, University of Illinois at Chicago, 833 S. Wood St. Chicago, Illinois 60612-7231.

² Both authors contributed equally to the work.

³ To whom correspondence should be addressed. Tel.: 33-561-175-569; Fax: 33-561-175-580; E-mail: daffe{at}ipbs.fr.

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