Targeted gene deletion of leishmania major UDP-galactopyranose mutase leads to attenuated virulence

B. Kleczka, A.C. Lamerz, G. van Zandbergen, M. Wiese

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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 glfmutant 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.
LanguageEnglish
Pages10498-10505
Number of pages7
JournalJournal of Biological Chemistry
VolumeVOL. 282
Issue number14
Publication statusPublished - 6 Apr 2007

Fingerprint

Leishmania major
Gene Deletion
Virulence
Genes
Metabolism
Gene encoding
Monosaccharides
Biosynthesis
Pathogens
Enzymes
Eukaryota
Anchors
Parasites
Membranes
Incidence
Growth
Pharmaceutical Preparations
lipophosphonoglycan
UDP-galactopyranose mutase

Keywords

  • galactofuranose
  • pathogens
  • biosynthesis
  • bacterial survival
  • pathogenesis
  • eukaryotic UDP-galactopyranose mutases
  • Leishmania major
  • GLF gene encoding
  • glycoinositolphospholipids
  • LPG

Cite this

Kleczka, B. ; Lamerz, A.C. ; van Zandbergen, G. ; Wiese, M. / Targeted gene deletion of leishmania major UDP-galactopyranose mutase leads to attenuated virulence. In: Journal of Biological Chemistry. 2007 ; Vol. VOL. 282, No. 14. pp. 10498-10505.
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Targeted gene deletion of leishmania major UDP-galactopyranose mutase leads to attenuated virulence. / Kleczka, B.; Lamerz, A.C.; van Zandbergen, G.; Wiese, M.

In: Journal of Biological Chemistry, Vol. VOL. 282, No. 14, 06.04.2007, p. 10498-10505.

Research output: Contribution to journalArticle

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T1 - Targeted gene deletion of leishmania major UDP-galactopyranose mutase leads to attenuated virulence

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AU - Lamerz, A.C.

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AB - 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 glfmutant 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.

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