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J. Biol. Chem., Vol. 278, Issue 42, 40842-40850, October 17, 2003

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Disruption of Cg-Ppm1, a Polyprenyl Monophosphomannose Synthase, and the Generation of Lipoglycan-less Mutants in Corynebacterium glutamicum^*

Kevin J. C. Gibson , Lothar Eggeling , William N. Maughan , Karin Krumbach , Sudagar S. Gurcha , Jérôme Nigou ¶, Germain Puzo ¶, Hermann Sahm  and Gurdyal S. Besra  ||

From the School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, the Institute for Biotechnologie 1, Research Centre Juelich, D-52425 Juelich, Germany, and the ^¶Department of Molecular Mechanisms of Mycobacterial Infections, Institut de Pharmacologie et de Biologie Structurale, CNRS, UMR 5089, 205 route de Narbonne, 31077 Toulouse cedex 4, France

The glycosyl donor, polyprenyl monophosphomannose (PPM), has been shown to be involved in the biosynthesis of the mycobacterial lipoglycans: lipomannan and lipoarabinomannan. The mycobacterial PPM synthase (Mt-ppm1) catalyzes the transfer of mannose from GDP-mannose to polyprenyl phosphates. Based on sequence homology to Mt-ppm1, we have identified the PPM synthase from Corynebacterium glutamicum. In the present study, we demonstrate that the corynebacterial synthase is composed of two distinct domains; a catalytic domain (Cg-ppm1) and a membrane domain (Cg-ppm2). Through the inactivation of Cg-ppm1, we observed a complex phenotype that included altered cell growth rate and inability to synthesize PPM molecules and lipoglycans. When Cg-ppm2 was deleted, no observable phenotype was noted, indicating the clear organization of the two domains. The complementation of the inactivated Cg-ppm1 strain with the corresponding mycobacterial enzyme (Mt-Ppm1/D2) led to the restoration of a wild type phenotype. The present study illustrates, for the first time, the generation of a lipoglycan-less mutant based on a molecular strategy in a member of the Corynebacterianeae family. Lipoglycans are important immunomodulatory molecules involved in determining the outcome of infection, and so the generation of defined mutants and their subsequent immunological characterization is timely.

Received for publication, July 23, 2003 , and in revised form, August 5, 2003.

^* This work was supported in part by Medical Research Council Grants G9901077 and G9901078 and by Wellcome Trust Grant 058972. 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.

^|| Jenner Research Fellow of the Lister Institute. To whom correspondence should be addressed. Tel.: 44-121-415-8125; Fax: 44-121-414-5925; E-mail: g.besra{at}bham.ac.uk.

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