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J. Biol. Chem., Vol. 279, Issue 18, 18824-18833, April 30, 2004

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PimF, a Mannosyltransferase of Mycobacteria, Is Involved in the Biosynthesis of Phosphatidylinositol Mannosides and Lipoarabinomannan^*

David C. Alexander, Joses R. W. Jones, Tracy Tan, Jeffrey M. Chen, and Jun Liu, A CIHR New Investigator

From the Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Phosphatidylinositol mannosides (PIMs) and their related molecules lipomannan (LM) and lipoarabinomannan (LAM) are important components of the mycobacterial cell wall. These molecules mediate host-pathogen interactions and exhibit immunomodulatory activities. The biosynthesis of these lipoglycans is not fully understood. In this study, we have identified a mycobacterial gene (Rv1500) that is involved in the synthesis of PIMs. We have named this gene pimF. Transposon mutagenesis of pimF of Mycobacterium marinum resulted in multiple phenotypes, including altered colony morphology, disappearance of tetracyl-PIM₇, and accumulation of tetraacyl-PIM₅. The syntheses of LAM and LM were also affected. In addition, the pimF mutant exhibited a defect during infection of cultured macrophage cells. Although the mutant was able to replicate and persist within macrophages, the initial cell entry step was inefficient. Transformation of the M. marinum mutant with the pimF homolog of Mycobacterium tuberculosis complemented all of the above mentioned phenotypes. These results provide evidence that PimF is a mannosyltransferase. However, sequence analysis indicates that PimF is distinct from mannosyltransferases involved in the early steps of PIM synthesis. PimF catalyzes the formation of high molecular weight PIMs, which are precursors for the synthesis of LAM and LM. As such, this work marks the first analysis of a mannosyltransferase involved in the later stages of PIM synthesis.

Received for publication, January 23, 2004

^* This work was supported by Canadian Institutes of Health Research (CIHR) Grant MOP-15107 and a grant from the National Sanitarium Association of Canada (to J. L.). -LAM antibody was provided through support from National Institutes of Health Grant N01-AI-75320. 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.

To whom correspondence should be addressed: 4382 Medical Sciences Bldg., Dept. of Medical Genetics and Microbiology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-946-5067; Fax: 416-978-6885; E-mail: jun.liu{at}utoronto.ca.

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