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J. Biol. Chem., Vol. 282, Issue 37, 27270-27276, September 14, 2007

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Genetic Basis for the Biosynthesis of Methylglucose Lipopolysaccharides in Mycobacterium tuberculosis^*

Gustavo Stadthagen, Tounkang Sambou, Marcelo Guerin^¶, Nathalie Barilone, Frédéric Boudou, Jana Korduláková¹, Patricia Charles, Pedro M. Alzari^¶, Anne Lemassu, Mamadou Daffé, Germain Puzo, Brigitte Gicquel, Michel Rivière, and Mary Jackson²

From the UnitédeGénétique Mycobactérienne and ^¶Unité de Biochimie Structurale, Institut Pasteur, 75015 Paris, France and the Département Mécanismes Moléculaires des Infections Mycobactériennes, Institut de Pharmacologie et de Biologie Structurale, CNRS, 31077 Toulouse, France

Mycobacteria produce two unusual polymethylated polysaccharides, the 6-O-methylglucosyl-containing lipopolysaccharides (MGLP) and the 3-O-methylmannose polysaccharides, which have been shown to regulate fatty acid biosynthesis in vitro. A cluster of genes dedicated to the synthesis of MGLP was identified in Mycobacterium tuberculosis and Mycobacterium smegmatis. Overexpression of the putative glycosyltransferase gene Rv3032 in M. smegmatis greatly stimulated MGLP production, whereas the targeted disruption of Rv3032 in M. tuberculosis and that of the putative methyltransferase gene MSMEG2349 in M. smegmatis resulted in a dramatic reduction in the amounts of MGLP synthesized and in the accumulation of precursors of these molecules. Disruption of Rv3032 also led to a significant decrease in the glycogen content of the tubercle bacillus, indicating that the product of this gene is likely to be involved in the elongation of more than one -(14)-glucan in this bacterium. Results thus suggest that Rv3032 encodes the -(14)-glucosyltransferase responsible for the elongation of MGLP, whereas MSMEG2349 encodes the O-methyltransferase required for the 6-O-methylation of these compounds.

Received for publication, March 28, 2007 , and in revised form, July 18, 2007.

^* This work was supported by the Institut Pasteur (GPH-Tuberculose), NIAAID, National Institutes of Health, Grant 5R01AI064798-3, European Commission Contract LSHP-CT-2005-018923 (NM4TB), Consejo Nacional de Ciencia y Tecnologia, Mexico, Fellowship 175523 (to G. S.), and the Heiser Program for Research in Leprosy and Tuberculosis postdoctoral fellowship (to J. K.). 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 Figs. 1-3.

¹ Present address: Dept. of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynska Dolina CH-1, 84215 Bratislava, Slovak Republic.

² To whom correspondence should be addressed: Dept. of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523-1682. Tel.: 970-491-3582; Fax: 970-491-1815; E-mail: Mary.Jackson{at}colostate.edu.

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