The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages

Sílvia Sanz; Borja López-Gutiérrez; Giulia Bandini; Sebastian Damerow; Sabrina Absalon; Rhoel R. Dinglasan; John Samuelson; Luis Izquierdo

doi:10.1038/srep37230

The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages

Sílvia Sanz, Borja López-Gutiérrez, Giulia Bandini, Sebastian Damerow, Sabrina Absalon, Rhoel R. Dinglasan, John Samuelson, Luis Izquierdo

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Abstract

Glycosylation is an important posttranslational protein modification in all eukaryotes. Besides glycosylphosphatidylinositol (GPI) anchors and N-glycosylation, O-fucosylation has been recently reported in key sporozoite proteins of the malaria parasite. Previous analyses showed the presence of GDP-fucose (GDP-Fuc), the precursor for all fucosylation reactions, in the blood stages of Plasmodium falciparum. The GDP-Fuc de novo pathway, which requires the action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose synthase (FS), is conserved in the parasite genome, but the importance of fucose metabolism for the parasite is unknown. To functionally characterize the pathway we generated a PfGMD mutant and analyzed its phenotype. Although the labelling by the fucose-binding Ulex europaeus agglutinin I (UEA-I) was completely abrogated, GDP-Fuc was still detected in the mutant. This unexpected result suggests the presence of an alternative mechanism for maintaining GDP-Fuc in the parasite. Furthermore, PfGMD null mutant exhibited normal growth and invasion rates, revealing that the GDP-Fuc de novo metabolic pathway is not essential for the development in culture of the malaria parasite during the asexual blood stages. Nonetheless, the function of this metabolic route and the GDP-Fuc pool that is generated during this stage may be important for gametocytogenesis and sporogonic development in the mosquito.

Original language	English
Article number	37230
Pages (from-to)	1-8
Number of pages	8
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep37230
Publication status	Published - 16 Nov 2016

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10.1038/srep37230Licence: CC BY

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Parasite Glycobiology and Anti-parasitic Strategies (GLYCOPAR)
Ferguson, M. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/12/13 → 30/11/16
Project: Research

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@article{ddf4b1e212c846e6bc7d5b9549034afa,

title = "The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages",

abstract = "Glycosylation is an important posttranslational protein modification in all eukaryotes. Besides glycosylphosphatidylinositol (GPI) anchors and N-glycosylation, O-fucosylation has been recently reported in key sporozoite proteins of the malaria parasite. Previous analyses showed the presence of GDP-fucose (GDP-Fuc), the precursor for all fucosylation reactions, in the blood stages of Plasmodium falciparum. The GDP-Fuc de novo pathway, which requires the action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose synthase (FS), is conserved in the parasite genome, but the importance of fucose metabolism for the parasite is unknown. To functionally characterize the pathway we generated a PfGMD mutant and analyzed its phenotype. Although the labelling by the fucose-binding Ulex europaeus agglutinin I (UEA-I) was completely abrogated, GDP-Fuc was still detected in the mutant. This unexpected result suggests the presence of an alternative mechanism for maintaining GDP-Fuc in the parasite. Furthermore, PfGMD null mutant exhibited normal growth and invasion rates, revealing that the GDP-Fuc de novo metabolic pathway is not essential for the development in culture of the malaria parasite during the asexual blood stages. Nonetheless, the function of this metabolic route and the GDP-Fuc pool that is generated during this stage may be important for gametocytogenesis and sporogonic development in the mosquito.",

author = "S{\'i}lvia Sanz and Borja L{\'o}pez-Guti{\'e}rrez and Giulia Bandini and Sebastian Damerow and Sabrina Absalon and Dinglasan, {Rhoel R.} and John Samuelson and Luis Izquierdo",

note = "LI thanks funding from Spanish Ministry of Economy (grants SAF2010-21069 and SAF2013-43656-R, supporting SS and BL-G) and from National Institutes of Health (grant 1R21AI115063-01, currently supporting SS, RRD and LI). LI is a member of the GlycoPar-EU FP7 funded Marie Curie Initial Training Network (GA 608295). The authors thank Hernando A. del Portillo and Carmen Fern{\'a}ndez Becerra for support, reagents and helpful discussions throughout this project. We thank Mike Ferguson for helpful discussions and access to LC-MS/MS systems to measure sugar nucleotides. We are also grateful to M. Ram{\'i}rez, M. Bernabeu, A. Cort{\'e}s and CCiTUB (Scientific and Technological Centers Universitat de Barcelona) for technical support, advice, assistance and useful suggestions. This work was funded by the Spanish Ministry of Economy (grants SAF2010-21069 and SAF2013-43656-R) and National Institutes of Health (grant 1R21AI115063-01).",

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month = nov,

day = "16",

doi = "10.1038/srep37230",

language = "English",

volume = "6",

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journal = "Scientific Reports",

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T1 - The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages

AU - Sanz, Sílvia

AU - López-Gutiérrez, Borja

AU - Bandini, Giulia

AU - Damerow, Sebastian

AU - Absalon, Sabrina

AU - Dinglasan, Rhoel R.

AU - Samuelson, John

AU - Izquierdo, Luis

N1 - LI thanks funding from Spanish Ministry of Economy (grants SAF2010-21069 and SAF2013-43656-R, supporting SS and BL-G) and from National Institutes of Health (grant 1R21AI115063-01, currently supporting SS, RRD and LI). LI is a member of the GlycoPar-EU FP7 funded Marie Curie Initial Training Network (GA 608295). The authors thank Hernando A. del Portillo and Carmen Fernández Becerra for support, reagents and helpful discussions throughout this project. We thank Mike Ferguson for helpful discussions and access to LC-MS/MS systems to measure sugar nucleotides. We are also grateful to M. Ramírez, M. Bernabeu, A. Cortés and CCiTUB (Scientific and Technological Centers Universitat de Barcelona) for technical support, advice, assistance and useful suggestions. This work was funded by the Spanish Ministry of Economy (grants SAF2010-21069 and SAF2013-43656-R) and National Institutes of Health (grant 1R21AI115063-01).

PY - 2016/11/16

Y1 - 2016/11/16

N2 - Glycosylation is an important posttranslational protein modification in all eukaryotes. Besides glycosylphosphatidylinositol (GPI) anchors and N-glycosylation, O-fucosylation has been recently reported in key sporozoite proteins of the malaria parasite. Previous analyses showed the presence of GDP-fucose (GDP-Fuc), the precursor for all fucosylation reactions, in the blood stages of Plasmodium falciparum. The GDP-Fuc de novo pathway, which requires the action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose synthase (FS), is conserved in the parasite genome, but the importance of fucose metabolism for the parasite is unknown. To functionally characterize the pathway we generated a PfGMD mutant and analyzed its phenotype. Although the labelling by the fucose-binding Ulex europaeus agglutinin I (UEA-I) was completely abrogated, GDP-Fuc was still detected in the mutant. This unexpected result suggests the presence of an alternative mechanism for maintaining GDP-Fuc in the parasite. Furthermore, PfGMD null mutant exhibited normal growth and invasion rates, revealing that the GDP-Fuc de novo metabolic pathway is not essential for the development in culture of the malaria parasite during the asexual blood stages. Nonetheless, the function of this metabolic route and the GDP-Fuc pool that is generated during this stage may be important for gametocytogenesis and sporogonic development in the mosquito.

AB - Glycosylation is an important posttranslational protein modification in all eukaryotes. Besides glycosylphosphatidylinositol (GPI) anchors and N-glycosylation, O-fucosylation has been recently reported in key sporozoite proteins of the malaria parasite. Previous analyses showed the presence of GDP-fucose (GDP-Fuc), the precursor for all fucosylation reactions, in the blood stages of Plasmodium falciparum. The GDP-Fuc de novo pathway, which requires the action of GDP-mannose 4,6-dehydratase (GMD) and GDP-L-fucose synthase (FS), is conserved in the parasite genome, but the importance of fucose metabolism for the parasite is unknown. To functionally characterize the pathway we generated a PfGMD mutant and analyzed its phenotype. Although the labelling by the fucose-binding Ulex europaeus agglutinin I (UEA-I) was completely abrogated, GDP-Fuc was still detected in the mutant. This unexpected result suggests the presence of an alternative mechanism for maintaining GDP-Fuc in the parasite. Furthermore, PfGMD null mutant exhibited normal growth and invasion rates, revealing that the GDP-Fuc de novo metabolic pathway is not essential for the development in culture of the malaria parasite during the asexual blood stages. Nonetheless, the function of this metabolic route and the GDP-Fuc pool that is generated during this stage may be important for gametocytogenesis and sporogonic development in the mosquito.

U2 - 10.1038/srep37230

DO - 10.1038/srep37230

M3 - Article

C2 - 27849032

SN - 2045-2322

VL - 6

SP - 1

EP - 8

JO - Scientific Reports

JF - Scientific Reports

M1 - 37230

ER -

The disruption of GDP-fucose de novo biosynthesis suggests the presence of a novel fucose-containing glycoconjugate in Plasmodium asexual blood stages

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