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

Considering the high incidence of galactofuranose (Galf) 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 Galf in bacterial survival or pathogenesis is e...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-04, Vol.282 (14), p.10498-10505
Main Authors: Kleczka, Barbara, Lamerz, Anne-Christin, van Zandbergen, Ger, Wenzel, Alexander, Gerardy-Schahn, Rita, Wiese, Martin, Routier, Françoise H.
Format: Article
Language:English
Subjects:
Animals
Galactose - analogs & derivatives
Galactose - metabolism
Gene Deletion
Glycolipids - biosynthesis
Glycolipids - genetics
Intramolecular Transferases - deficiency
Intramolecular Transferases - metabolism
Leishmania major
Leishmania major - enzymology
Leishmania major - genetics
Leishmania major - pathogenicity
Leishmaniasis, Cutaneous - drug therapy
Leishmaniasis, Cutaneous - enzymology
Leishmaniasis, Cutaneous - genetics
Phospholipids - biosynthesis
Phospholipids - genetics
Protozoan Proteins - genetics
Protozoan Proteins - metabolism
Uridine Diphosphate - analogs & derivatives
Uridine Diphosphate - metabolism
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Summary:Considering the high incidence of galactofuranose (Galf) 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 Galf 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 Galf metabolism by providing UDP-Galf to all galactofuranosyltransferases. In this work, the therapeutical potential of Galf metabolism in Leishmania major was hence evaluated by targeted replacement of the GLF gene encoding UDP-galactopyranose mutase. In L. major, Galf 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M700023200