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J. Biol. Chem., Vol. 283, Issue 11, 6773-6782, March 14, 2008

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Analysis of a New Mannosyltransferase Required for the Synthesis of Phosphatidylinositol Mannosides and Lipoarbinomannan Reveals Two Lipomannan Pools in Corynebacterineae^*

David J. Lea-Smith¹², Kirstee L. Martin¹, James S. Pyke, Dedreia Tull, Malcolm J. McConville³⁴⁵, Ross L. Coppel³⁴, and Paul K. Crellin³⁶

From the Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, and Victorian Bioinformatics Consortium, Department of Microbiology, Monash University, Clayton, Victoria 3800 and the Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Sciences and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia

The cell walls of the Corynebacterineae, which includes the important human pathogen Mycobacterium tuberculosis, contain two major lipopolysaccharides, lipoarabinomannan (LAM) and lipomannan (LM). LAM is assembled on a subpool of phosphatidylinositol mannosides (PIMs), whereas the identity of the LM lipid anchor is less well characterized. In this study we have identified a new gene (Rv2188c in M. tuberculosis and NCgl2106 in Corynebacterium glutamicum) that encodes a mannosyltransferase involved in the synthesis of the early dimannosylated PIM species, acyl-PIM2, and LAM. Disruption of the C. glutamicum NCgl2106 gene resulted in loss of synthesis of AcPIM2 and accumulation of the monomannosylated precursor, AcPIM1. The synthesis of a structurally unrelated mannolipid, Gl-X, was unaffected. The synthesis of AcPIM2 in C. glutamicum NCgl2106 was restored by complementation with M. tuberculosis Rv2188c. In vivo labeling of the mutant with [³H]Man and in vitro labeling of membranes with GDP-[³H]Man confirmed that NCgl2106/Rv2188c catalyzed the second mannose addition in PIM biosynthesis, a function previously ascribed to PimB/Rv0557. The C. glutamicum NCgl2106 mutant lacked mature LAM but unexpectedly still synthesized the major pool of LM. Biochemical analyses of the LM core indicated that this lipopolysaccharide was assembled on Gl-X. These data suggest that NCgl2106/Rv2188c and the previously studied PimB/Rv0557 transfer mannose residues to distinct mannoglycolipids that act as precursors for LAM and LM, respectively.

Received for publication, August 27, 2007 , and in revised form, December 19, 2007.

^* This work was supported in part by the Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics and the National Health and Medical Research Council of Australia. 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 Both authors should be considered as equal first authors.

² Supported by an Australian postgraduate award.

³ These authors should be considered as equal senior authors.

⁴ Supported by the Howard Hughes Medical Institute International Scholars Program.

⁵ National Health and Medical Research Council Principal Research Fellow.

⁶ To whom correspondence should be addressed. Tel.: 61-3-9905-1468; Fax: 61-3-9905-4811; E-mail: paul.crellin{at}med.monash.edu.au.

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