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J. Biol. Chem., Vol. 282, Issue 28, 20705-20714, July 13, 2007

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Molecular Recognition and Interfacial Catalysis by the Essential Phosphatidylinositol Mannosyltransferase PimA from Mycobacteria^*

Marcelo E. Guerin, Jana Kordulakova^¶, Francis Schaeffer, Zuzana Svetlikova^¶, Alejandro Buschiazzo, David Giganti^||, Brigitte Gicquel, Katarina Mikusova^¶, Mary Jackson, and Pedro M. Alzari¹

From the Unité de Biochimie Structurale (CNRS URA 2185), UnitédeGénétique Mycobactérienne, and ^||Unité de Bioinformatique Structurale, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France and ^¶Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina, 84215 Bratislava, Slovakia

Mycobacterial phosphatidylinositol mannosides (PIMs) and metabolically derived cell wall lipoglycans play important roles in host-pathogen interactions, but their biosynthetic pathways are poorly understood. Here we focus on Mycobacterium smegmatis PimA, an essential enzyme responsible for the initial mannosylation of phosphatidylinositol. The structure of PimA in complex with GDP-mannose shows the two-domain organization and the catalytic machinery typical of GT-B glycosyltransferases. PimA is an amphitrophic enzyme that binds mono-disperse phosphatidylinositol, but its transferase activity is stimulated by high concentrations of non-substrate anionic surfactants, indicating that the early stages of PIM biosynthesis involve lipid-water interfacial catalysis. Based on structural, calorimetric, and mutagenesis studies, we propose a model wherein PimA attaches to the membrane through its N-terminal domain, and this association leads to enzyme activation. Our results reveal a novel mode of phosphatidylinositol recognition and provide a template for the development of potential antimycobacterial compounds.

Received for publication, March 9, 2007 , and in revised form, May 11, 2007.

The atomic coordinates and structure factors (code 2GEJ and 2GEK) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by grants from the Institut Pasteur (GPH-5 Tuberculose), NIAID, National Institutes of Health Grant AI64798, Slovak Grant Agency VEGA 1/2324/05, European Union projects "New Medicines for Tuberculosis" (contract LSHP-CT-2005-018923), and "Structural proteomics in Europe" (contract QLG2-CT-2002-00988). 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.

¹ To whom correspondence should be addressed. Tel.: 33-145688607; Fax: 33-145688604; E-mail: alzari{at}pasteur.fr.

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