Genes for glycosylphosphatidylinositol toxin biosynthesis in Plasmodium falciparum.
About 2.5 million people die of Plasmodium falciparum malaria every year. Fatalities are associated with systemic and organ-specific inflammation initiated by a parasite toxin. Recent studies show that glycosylphosphatidylinositol (GPI) functions as the dominant parasite toxin in the context of infection. GPIs also serve as membrane anchors for several of the most important surface antigens of parasite invasive stages. GPI anchoring is a complex posttranslational modification produced through the coordinated action of a multicomponent biosynthetic pathway. Here we present eight new genes of P. falciparum selected for encoding homologs of proteins essential for GPI synthesis: PIG-A, PIG-B, PIG-M, PIG-O, GPI1, GPI8, GAA-1, and DPM1. We describe the experimentally verified mRNA and predicted amino acid sequences and in situ localization of the gene products to the parasite endoplasmic reticulum. Moreover, we show preliminary evidence for the PIG-L and PIG-C genes. The biosynthetic pathway of the malaria parasite GPI offers potential targets for drug development and may be useful for studying parasite cell biology and the molecular basis for the pathophysiology of parasitic diseases.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.
Mauro
M
Delorenzi
Adrienne
A
Sexton
Hosam
H
Shams-Eldin
Ralph T
RT
Schwarz
Terry
T
Speed
Louis
L
Schofield
D000107:Acetylation; D000117:Acetylglucosamine / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics; D016054:DNA, Protozoan; D017125:Genes, Protozoan; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis*; D006801:Humans; D008364:Mannosyltransferases / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D010716:Phosphatidylinositols / Q000378:metabolism; D010963:Plasmodium falciparum / Q000235:genetics*; D015800:Protozoan Proteins / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016054:DNA, Protozoan; C093316:GPAA1 protein, human; C455320:GPI1 protein, Plasmodium falciparum; D017261:Glycosylphosphatidylinositols; C486253:Gpaa1 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C485855:PIG-O protein, Plasmodium falciparum; C491190:PIGK protein, human; C485854:PIGO protein, human; D010716:Phosphatidylinositols; D015800:Protozoan Proteins; D029701:Saccharomyces cerevisiae Proteins; C080086:phosphatidylinositol glycan-class A protein; D014537:Uridine Diphosphate N-Acetylglucosamine; C068701:KRE2 protein, S cerevisiae; D008364:Mannosyltransferases; C040827:alpha 1-4-mannosyltransferase; C022755:dolichyl-phosphate beta-D-mannosyltransferase; D000117:Acetylglucosamine