Identification of a species-specific inhibitor of glycosylphosphatidylinositol synthesis.
Glycosylphosphatidylinositol (GPI)-anchoring represents a mechanism for attaching proteins to the cell surface that is used among all eukaryotes. A common core structure, EthN-P-Man3-GlcN-PI, is synthesized by sequential transfer of sugars and ethanolamine-P to PI and is highly conserved between organisms. We have screened for natural compounds that inhibit GPI-anchoring in yeast and have identified a terpenoid lactone, YW3548, that specifically blocks the addition of the third mannose to the intermediate structure Man2-GlcN-acyIPI. Consistent with the block in GPI synthesis, YW3548 prevents the incorporation of [3H]myo-inositol into proteins, transport of GPI-anchored proteins to the Golgi and is toxic. The compound inhibits the same step of GPI synthesis in mammalian cells, but has no significant activity in protozoa. These results suggest that despite the conserved core structure, the GPI biosynthetic machinery may be different enough between mammalian and protozoa to represent a target for anti-protozoan chemotherapy.
Sütterlin
C
C
Biozentrum of the University of Basel, Switzerland.
Horvath
A
A
Gerold
P
P
Schwarz
R T
RT
Wang
Y
Y
Dreyfuss
M
M
Riezman
H
H
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism; D002240:Carbohydrate Sequence; D002462:Cell Membrane / Q000187:drug effects; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D017261:Glycosylphosphatidylinositols / Q000096:biosynthesis*; D006056:Golgi Apparatus / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D016399:Lymphoma, T-Cell / Q000473:pathology; D008358:Mannose / Q000378:metabolism; D008359:Mannose-6-Phosphate Isomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000378:metabolism; D010247:Paramecium / Q000187:drug effects / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000648:ultrastructure; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D013045:Species Specificity; D013379:Substrate Specificity; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000648:ultrastructure; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015003:Yeasts / Q000737:chemistry*
D000981:Antiprotozoal Agents; D005656:Fungal Proteins; C066709:GAS1 protein, S cerevisiae; D017261:Glycosylphosphatidylinositols; D007783:Lactones; D008562:Membrane Glycoproteins; D008563:Membrane Lipids; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D029701:Saccharomyces cerevisiae Proteins; D013729:Terpenes; C109532:YW 3548; D007294:Inositol; C068701:KRE2 protein, S cerevisiae; D008364:Mannosyltransferases; D008359:Mannose-6-Phosphate Isomerase; D008358:Mannose