Differential effect of 1,10-phenanthroline on mammalian, yeast, and parasite glycosylphosphatidylinositol anchor synthesis.
Glycosylphosphatidylinositol (GPI) anchoring of proteins to the plasma membrane is a common mechanism utilized by all eukaryotes including mammals, yeast, and the Trypanosoma brucei parasite. We have previously shown that in mammals phenanthroline (PNT) blocks the attachment of phosphoethanolamine (P-EthN) groups to mannose residues in GPI anchor intermediates, thus preventing the synthesis of mammalian GPI anchors. Therefore, PNT is likely to inhibit GPI-phosphoethanolamine transferases (GPI-PETs). Here we report that in yeast, PNT also inhibits the synthesis of the GPI anchor as well as GPI-anchored proteins. Interestingly, the mechanism of PNT inhibition of GPI synthesis is different from that of YW3548, another putative GPI-PET inhibitor. In contrast to mammals and yeast, the synthesis of GPIs in T. brucei is not affected by PNT. Our results indicate that the T. brucei GPI-PET could be a potential target for antiparasitic drugs.
Sevlever
D
D
Department of Neurosciences, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. sevlever.daniel@mayo.edu
Mann
K J
KJ
Medof
M E
ME
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004982:Ethanolaminephosphotransferase / Q000037:antagonists & inhibitors; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis*; D006367:HeLa Cells; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008956:Models, Chemical; D010618:Phenanthrolines / Q000494:pharmacology*; D013045:Species Specificity; D013729:Terpenes / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology
D004791:Enzyme Inhibitors; D017261:Glycosylphosphatidylinositols; D007783:Lactones; D010618:Phenanthrolines; D013729:Terpenes; C109532:YW 3548; D004982:Ethanolaminephosphotransferase; D015032:Zinc; C025205:1,10-phenanthroline