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J. Biol. Chem., Vol. 280, Issue 22, 21645-21652, June 3, 2005

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Compartmentalization of Lipid Biosynthesis in Mycobacteria^*

Yasu S. Morita, René Velasquez, Ellen Taig¶, Ross F. Waller, John H. Patterson, Dedreia Tull, Spencer J. Williams||, Helen Billman-Jacobe¶, and Malcolm J. McConville, A National Health and Medical Research Council Principle Research Fellow and Howard Hughes International Research Fellow**

From the Department of Biochemistry and Molecular Biology, the ^¶Department of Microbiology and Immunology, and the ^||School of Chemistry, University of Melbourne, The B1021 Molecular Sciences and Biotechnology Institute, 30 Flemington Road, Parkville, Victoria 3010, Australia

The plasma membrane of Mycobacterium sp. is the site of synthesis of several distinct classes of lipids that are either retained in the membrane or exported to the overlying cell envelope. Here, we provide evidence that enzymes involved in the biosynthesis of two major lipid classes, the phosphatidylinositol mannosides (PIMs) and aminophospholipids, are compartmentalized within the plasma membrane. Enzymes involved in the synthesis of early PIM intermediates were localized to a membrane subdomain termed PM_f, that was clearly resolved from the cell wall by isopyknic density centrifugation and amplified in rapidly dividing Mycobacterium smegmatis. In contrast, the major pool of apolar PIMs and enzymes involved in polar PIM biosynthesis were localized to a denser fraction that contained both plasma membrane and cell wall markers (PM-CW). Based on the resistance of the PIMs to solvent extraction in live but not lysed cells, we propose that polar PIM biosynthesis occurs in the plasma membrane rather than the cell wall component of the PM-CW. Enzymes involved in phosphatidylethanolamine biosynthesis also displayed a highly polarized distribution between the PM_f and PM-CW fractions. The PM_f was greatly reduced in non-dividing cells, concomitant with a reduction in the synthesis and steady-state levels of PIMs and amino-phospholipids and the redistribution of PM_f marker enzymes to non-PM-CW fractions. The formation of the PM_f and recruitment of enzymes to this domain may thus play a role in regulating growth-specific changes in the biosynthesis of membrane and cell wall lipids.

Received for publication, December 17, 2004 , and in revised form, March 24, 2005.

^* This work was supported in part by an NH and MRC Program grant, by the United Nations Development Programme/World Health Organization Special Programme for Research and Training in Tropical Diseases, and by a Wellcome Trust major equipment grant for the gas chromatography-mass spectrometry. 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 a long term postdoctoral fellowship from the International Human Frontier Science Program Organization. Current address: Dept. of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871 Japan.

^** To whom correspondence should be addressed. Tel.: 61-3-8344-2342; Fax: 61-3-8344-2224; E-mail: malcolmm{at}unimelb.edu.au.

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