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J. Biol. Chem., Vol. 282, Issue 14, 10498-10505, April 6, 2007

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Targeted Gene Deletion of Leishmania major UDP-galactopyranose Mutase Leads to Attenuated Virulence^*

Barbara Kleczka, Anne-Christin Lamerz, Ger van Zandbergen, Alexander Wenzel, Rita Gerardy-Schahn, Martin Wiese^¶, and Françoise H. Routier¹

From the Medizinische Hochschule Hannover, Carl-Neuberg Strasse 1, 30625 Hannover, Germany, Institute for Medical Microbiology and Hygiene, Ratzeburger Allee 160, 23538 Luebeck, Germany, and ^¶Bernhard Nocht Institute for Tropical Medicine, Bernhard Nocht Strasse 74, 20359 Hamburg, Germany

Considering the high incidence of galactofuranose (Gal_f) in pathogens and its absence from higher eukaryotes, the enzymes involved in the biosynthesis of this unusual monosaccharide appear as attractive drug targets. However, although the importance of Gal_f in bacterial survival or pathogenesis is established, its role in eukaryotic pathogens is still undefined. Recently, we reported the identification and characterization of the first eukaryotic UDP-galactopyranose mutases. This enzyme holds a central role in Gal_f metabolism by providing UDP-Gal_f to all galactofuranosyltransferases. In this work, the therapeutical potential of Gal_f metabolism in Leishmania major was hence evaluated by targeted replacement of the GLF gene encoding UDP-galactopyranose mutase. In L. major, Gal_f is present in the membrane anchor of the lipophosphoglycan (LPG) and in glycoinositolphospholipids. Accordingly, the generated glf^- mutant is deficient in LPG backbone and expresses truncated glycoinositolphospholipids. These structural changes do not influence the in vitro growth of the parasite but lead to an attenuation of virulence comparable with that observed with a mutant exclusively deficient in LPG.

Received for publication, January 2, 2007 , and in revised form, February 6, 2007.

^* 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 To whom correspondence should be addressed. Tel.: 49-511-5329807; Fax: 49-511-5323956; E-mail: Routier.Francoise{at}mh-hannover.de.

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