Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages.
UDP-N-acetylglucosamine (UDP-GlcNAc) is a crucial sugar nucleotide for glycan synthesis in eukaryotes. In the malaria parasite Plasmodium falciparum, UDP-GlcNAc is synthesized via the hexosamine biosynthetic pathway (HBP) and is essential for glycosylphosphatidylinositol (GPI) anchor production, the...
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| Format: | Article |
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Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1012832 |
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| author | María Pía Alberione Yunuen Avalos-Padilla Gabriel W Rangel Miriam Ramírez Tais Romero-Uruñuela Àngel Fenollar Jonathan Ortega-Barrionuevo Marcell Crispim Terry K Smith Manuel Llinás Luis Izquierdo |
| author_facet | María Pía Alberione Yunuen Avalos-Padilla Gabriel W Rangel Miriam Ramírez Tais Romero-Uruñuela Àngel Fenollar Jonathan Ortega-Barrionuevo Marcell Crispim Terry K Smith Manuel Llinás Luis Izquierdo |
| author_sort | María Pía Alberione |
| collection | DOAJ |
| description | UDP-N-acetylglucosamine (UDP-GlcNAc) is a crucial sugar nucleotide for glycan synthesis in eukaryotes. In the malaria parasite Plasmodium falciparum, UDP-GlcNAc is synthesized via the hexosamine biosynthetic pathway (HBP) and is essential for glycosylphosphatidylinositol (GPI) anchor production, the most prominent form of protein glycosylation in the parasite. In this study, we explore a conditional knockout of glucosamine-6-phosphate N-acetyltransferase (PfGNA1), a key HBP enzyme. PfGNA1 depletion led to significant disruptions in HBP metabolites, impairing GPI biosynthesis and causing mislocalization of the merozoite surface protein 1 (MSP1), the most abundant GPI-anchored protein in the parasite. Furthermore, parasites were arrested at the schizont stage, exhibiting severe segmentation defects and an incomplete rupture of the parasitophorous vacuole membrane (PVM), preventing egress from host red blood cells. Our findings demonstrate the critical role of HBP and GPI biosynthesis in P. falciparum asexual blood stage development and underscore the potential of targeting these pathways as a therapeutic strategy against malaria. |
| format | Article |
| id | doaj-art-3ef2a8317ad544ca8d430e4ba49da0f6 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-3ef2a8317ad544ca8d430e4ba49da0f62025-08-20T03:50:49ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-07-01217e101283210.1371/journal.ppat.1012832Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages.María Pía AlberioneYunuen Avalos-PadillaGabriel W RangelMiriam RamírezTais Romero-UruñuelaÀngel FenollarJonathan Ortega-BarrionuevoMarcell CrispimTerry K SmithManuel LlinásLuis IzquierdoUDP-N-acetylglucosamine (UDP-GlcNAc) is a crucial sugar nucleotide for glycan synthesis in eukaryotes. In the malaria parasite Plasmodium falciparum, UDP-GlcNAc is synthesized via the hexosamine biosynthetic pathway (HBP) and is essential for glycosylphosphatidylinositol (GPI) anchor production, the most prominent form of protein glycosylation in the parasite. In this study, we explore a conditional knockout of glucosamine-6-phosphate N-acetyltransferase (PfGNA1), a key HBP enzyme. PfGNA1 depletion led to significant disruptions in HBP metabolites, impairing GPI biosynthesis and causing mislocalization of the merozoite surface protein 1 (MSP1), the most abundant GPI-anchored protein in the parasite. Furthermore, parasites were arrested at the schizont stage, exhibiting severe segmentation defects and an incomplete rupture of the parasitophorous vacuole membrane (PVM), preventing egress from host red blood cells. Our findings demonstrate the critical role of HBP and GPI biosynthesis in P. falciparum asexual blood stage development and underscore the potential of targeting these pathways as a therapeutic strategy against malaria.https://doi.org/10.1371/journal.ppat.1012832 |
| spellingShingle | María Pía Alberione Yunuen Avalos-Padilla Gabriel W Rangel Miriam Ramírez Tais Romero-Uruñuela Àngel Fenollar Jonathan Ortega-Barrionuevo Marcell Crispim Terry K Smith Manuel Llinás Luis Izquierdo Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages. PLoS Pathogens |
| title | Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages. |
| title_full | Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages. |
| title_fullStr | Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages. |
| title_full_unstemmed | Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages. |
| title_short | Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages. |
| title_sort | hexosamine biosynthesis disruption impairs gpi production and arrests plasmodium falciparum growth at schizont stages |
| url | https://doi.org/10.1371/journal.ppat.1012832 |
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