A choline-releasing glycerophosphodiesterase essential for phosphatidylcholine biosynthesis and blood stage development in the malaria parasite
- The Francis Crick Institute, United Kingdom
- Centre for Structural Systems Biology, Germany
- Bernhard Nocht Institute for Tropical Medicine, Germany
Abstract
The malaria parasite Plasmodium falciparum synthesizes significant amounts of phospholipids to meet the demands of replication within red blood cells. De novo phosphatidylcholine (PC) biosynthesis via the Kennedy pathway is essential, requiring choline that is primarily sourced from host serum lysophosphatidylcholine (lysoPC). LysoPC also acts as an environmental sensor to regulate parasite sexual differentiation. Despite these critical roles for host lysoPC, the enzyme(s) involved in its breakdown to free choline for PC synthesis are unknown. Here we show that a parasite glycerophosphodiesterase (PfGDPD) is indispensable for blood stage parasite proliferation. Exogenous choline rescues growth of PfGDPD-null parasites, directly linking PfGDPD function to choline incorporation. Genetic ablation of PfGDPD reduces choline uptake from lysoPC, resulting in depletion of several PC species in the parasite, whilst purified PfGDPD releases choline from glycerophosphocholine in vitro. Our results identify PfGDPD as a choline-releasing glycerophosphodiesterase that mediates a critical step in PC biosynthesis and parasite survival.
Data availability
Sequencing data have been deposited in ENA under Project PRJEB55180.All data generated or analysed are included in the manuscript or provided as source data files.All source codes are available via github - https://github.com/a2g1n/GDPDxcute.
Article and author information
Author details
Abhinay Ramaprasad
Paul-Christian Burda
Tim Wolf Gilberger
Michael J Blackman
Funding
H2020 Marie Skłodowska-Curie Actions (751865)
- Abhinay Ramaprasad
Wellcome Trust (20318/A/20/Z)
- Michael J Blackman
Cancer Research UK (CC2129)
- Abhinay Ramaprasad
- Enrica Calvani
- Aaron J Sait
- Susana Alejandra Palma-Duran
- Chrislaine Withers-Martinez
- Fiona Hackett
- James Macrae
- Lucy Collinson
- Michael J Blackman
Medical Research Council (CC2129)
- Abhinay Ramaprasad
- Enrica Calvani
- Aaron J Sait
- Susana Alejandra Palma-Duran
- Chrislaine Withers-Martinez
- Fiona Hackett
- James Macrae
- Lucy Collinson
- Michael J Blackman
Wellcome Trust (CC2129)
- Abhinay Ramaprasad
- Enrica Calvani
- Aaron J Sait
- Susana Alejandra Palma-Duran
- Chrislaine Withers-Martinez
- Fiona Hackett
- James Macrae
- Lucy Collinson
- Michael J Blackman
Wellcome Trust (ISSF2)
- Michael J Blackman
Deutsche Forschungsgemeinschaft (414222880)
- Paul-Christian Burda
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Malcolm J McConville, The University of Melbourne, Australia
Version history
- Preprint posted: June 14, 2022 (view preprint)
- Received: July 27, 2022
- Accepted: December 23, 2022
- Accepted Manuscript published: December 28, 2022 (version 1)
- Version of Record published: January 30, 2023 (version 2)
Copyright
© 2022, Ramaprasad et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A choline-releasing glycerophosphodiesterase essential for phosphatidylcholine biosynthesis and blood stage development in the malaria parasite
eLife 11:e82207.
https://doi.org/10.7554/eLife.82207
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