Developmentally regulated sphingolipid synthesis in African trypanosomes.

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  • Additional Information
    • Source:
      Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 8712028 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2958 (Electronic) Linking ISSN: 0950382X NLM ISO Abbreviation: Mol Microbiol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford, OX ; Boston, MA : Blackwell Scientific Publications, c1987-
    • Subject Terms:
      Sphingolipids/*biosynthesis ; Trypanosoma brucei brucei/*chemistry ; Trypanosoma brucei brucei/*physiology; Africa ; Amino Acid Sequence ; Animals ; Gene Expression ; Gene Silencing ; Glycosphingolipids/isolation & purification ; Humans ; Leishmania/genetics ; Ligases/antagonists & inhibitors ; Ligases/genetics ; Ligases/metabolism ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Protozoan Proteins/antagonists & inhibitors ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism ; Sequence Alignment ; Sphingomyelins/isolation & purification ; Trypanosoma brucei brucei/isolation & purification
    • Abstract:
      Sphingolipids are essential components of eukaryotic membranes, and many unicellular eukaryotes, including kinetoplastid protozoa, are thought to synthesize exclusively inositol phosphorylceramide (IPC). Here we characterize sphingolipids from Trypanosoma brucei, and a trypanosome sphingolipid synthase gene family (TbSLS1-4) that is orthologous to Leishmania IPC synthase. Procyclic trypanosomes contain IPC, but also sphingomyelin, while surprisingly bloodstream-stage parasites contain sphingomyelin and ethanolamine phosphorylceramide (EPC), but no detectable IPC. In vivo fluorescent ceramide labelling confirmed stage-specific biosynthesis of both sphingomyelin and IPC. Expression of TbSLS4 in Leishmania resulted in production of sphingomyelin and EPC suggesting that the TbSLS gene family has bi-functional synthase activity. RNAi silencing of TbSLS1-4 in bloodstream trypanosomes led to rapid growth arrest and eventual cell death. Ceramide levels were increased more than threefold by silencing suggesting a toxic downstream effect mediated by this potent intracellular messenger. Topology predictions support a revised six-transmembrane domain model for the kinetoplastid sphingolipid synthases consistent with the proposed mammalian sphingomyelin synthase structure. This work reveals novel diversity and regulation in sphingolipid metabolism in this important group of human parasites.
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    • Grant Information:
      T32 AI055397-05 United States AI NIAID NIH HHS; P60-DK20579 United States DK NIDDK NIH HHS; P30 DK056341-08 United States DK NIDDK NIH HHS; R01 AI031078 United States AI NIAID NIH HHS; R01AI031078 United States AI NIAID NIH HHS; R01 AI035739 United States AI NIAID NIH HHS; P60 DK020579 United States DK NIDDK NIH HHS; T32 AI055397-06 United States AI NIAID NIH HHS; P30 DK056341 United States DK NIDDK NIH HHS; P30 DK056341-07 United States DK NIDDK NIH HHS; T32 GM007067-33 United States GM NIGMS NIH HHS; R01-AI35739 United States AI NIAID NIH HHS; R01 AI035739-14 United States AI NIAID NIH HHS; United Kingdom WT_ Wellcome Trust; T32 AI055397 United States AI NIAID NIH HHS; P41 RR000954 United States RR NCRR NIH HHS; T32 GM007067 United States GM NIGMS NIH HHS; P41-RR00954 United States RR NCRR NIH HHS; P30-DK56341 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (Glycosphingolipids)
      0 (Protozoan Proteins)
      0 (Sphingolipids)
      0 (Sphingomyelins)
      0 (inositolphosphoceramides)
      112130-78-6 (ceramide phosphoethanolamine)
      EC 6.- (Ligases)
    • Publication Date:
      Date Created: 20080814 Date Completed: 20081217 Latest Revision: 20230514
    • Publication Date:
      20250114
    • Accession Number:
      PMC2629665
    • Accession Number:
      10.1111/j.1365-2958.2008.06393.x
    • Accession Number:
      18699867