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J. Biol. Chem., Vol. 281, Issue 35, 25143-25155, September 1, 2006

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PimE Is a Polyprenol-phosphate-mannose-dependent Mannosyltransferase That Transfers the Fifth Mannose of Phosphatidylinositol Mannoside in Mycobacteria^*

Yasu S. Morita¹, Chubert B. C. Sena, Ross F. Waller, Ken Kurokawa^¶, M. Fleur Sernee^||, Fumiki Nakatani, Ruth E. Haites^**, Helen Billman-Jacobe^**, Malcolm J. McConville^||, Yusuke Maeda, and Taroh Kinoshita²

From the Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, the Plant Cell Biology Research Centre, School of Botany, the ^||Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, and the ^**Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia, and the ^¶Laboratory of Comparative Genomics, Graduate School of Information Science, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan

Phosphatidylinositol mannosides (PIMs) are a major class of glycolipids in all mycobacteria. AcPIM2, a dimannosyl PIM, is both an end product and a precursor for polar PIMs, such as hexamannosyl PIM (AcPIM6) and the major cell wall lipoglycan, lipoarabinomannan (LAM). The mannosyltransferases that convert AcPIM2 to AcPIM6 or LAM are dependent on polyprenol-phosphate-mannose (PPM), but have not yet been characterized. Here, we identified a gene, termed pimE that is present in all mycobacteria, and is required for AcPIM6 biosynthesis. PimE was initially identified based on homology with eukaryotic PIG-M mannosyltransferases. PimE-deleted Mycobacterium smegmatis was defective in AcPIM6 synthesis, and accumulated the tetramannosyl PIM, AcPIM4. Loss of PimE had no affect on cell growth or viability, or the biosynthesis of other intracellular and cell wall glycans. However, changes in cell wall hydrophobicity and plasma membrane organization were detected, suggesting a role for AcPIM6 in the structural integrity of the cell wall and plasma membrane. These defects were corrected by ectopic expression of the pimE gene. Metabolic pulse-chase radiolabeling and cell-free PIM biosynthesis assays indicated that PimE catalyzes the 1,2-mannosyl transfer for the AcPIM5 synthesis. Mutation of an Asp residue in PimE that is conserved in and required for the activity of human PIG-M resulted in loss of PIM-biosynthetic activity, indicating that PimE is the catalytic component. Finally, PimE was localized to a distinct membrane fraction enriched in AcPIM4–6 biosynthesis. Taken together, PimE represents the first PPM-dependent mannosyl-transferase shown to be involved in PIM biosynthesis, where it mediates the fifth mannose transfer.

Received for publication, May 2, 2006 , and in revised form, June 13, 2006.

Addendum—During the review of this manuscript, the following independent group (54) reported the identification of another mannosyltransferase not detected in our bioinformatics search. This enzyme is involved in the elaboration of terminal mannose capping of lipoarabinomannan found in pathogenic mycobacteria.

^* This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Core Research for Evolutional Science and Technology, Japan Science and Technology Agency. 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 Supported by an International Human Frontier Science Program postdoctoral fellowship and the Uehara Memorial Foundation.

² To whom correspondence should be addressed: Dept. of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-8328; Fax: 81-6-6875-5233; E-mail: tkinoshi{at}biken.osaka-u.ac.jp.

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