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J. Biol. Chem., Vol. 280, Issue 12, 10981-10987, March 25, 2005

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Function of Phosphatidylinositol in Mycobacteria^*

Ruth E. Haites, Yasu S. Morita¶||, Malcolm J. McConville¶**, and Helen Billman-Jacobe**

From the Departments of Microbiology and Immunology and ^¶Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia

Phosphatidylinositol (PI) is an abundant phospholipid in the cytoplasmic membrane of mycobacteria and the precursor for more complex glycolipids, such as the PI mannosides (PIMs) and lipoarabinomannan (LAM). To investigate whether the large steady-state pools of PI and apolar PIMs are required for mycobacterial growth, we have generated a Mycobacterium smegmatis inositol auxotroph by disruption of the ino1 gene. The ino1 mutant displayed wild-type growth rates and steady-state levels of PI, PIM, and LAM when grown in the presence of 1 mM inositol. The non-dividing ino1 mutant was highly resistant to inositol starvation, reflecting the slow turnover of inositol lipids in this stage. In contrast, dilution of growing or stationary-phase ino1 mutant in inositol-free medium resulted in the rapid depletion of PI and apolar PIMs. Whereas depletion of these lipids was not associated with loss of viability, subsequent depletion of polar PIMs coincided with loss of major cell wall components and cell viability. Metabolic labeling experiments confirmed that the large pools of PI and apolar PIMs were used to sustain polar PIM and LAM biosynthesis during inositol limitation. They also showed that under non-limiting conditions, PI is catabolized via lyso-PI. These data suggest that large pools of PI and apolar PIMs are not essential for membrane integrity but are required to sustain polar PIM biosynthesis, which is essential for mycobacterial growth.

Received for publication, November 30, 2004 , and in revised form, December 27, 2004.

^* This work was supported in part by grants from the National Health and Medical Research Council (Australia) and the World Health Organization Special Programme for Research and Training in Tropical Diseases. 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.

Supported by an Australian Postgraduate Award.

^|| Supported by the Human Frontier Science Program as a long-term postdoctoral fellow.

^** Both authors contributed equally to this work.

A National Health and Medical Research Council Principle Research Fellow and Howard Hughes International Research Fellow.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia. Tel.: 61-3-8344-5698; E-mail: hbj{at}unimelb.edu.au.

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