A choline-releasing glycerophosphodiesterase essential for phosphatidylcholine biosynthesis and blood stage development in the malaria parasite

  1. Abhinay Ramaprasad
  2. Paul-Christian Burda
  3. Enrica Calvani
  4. Aaron J Sait
  5. Susana Alejandra Palma-Duran
  6. Chrislaine Withers-Martinez
  7. Fiona Hackett
  8. James Macrae
  9. Lucy Collinson
  10. Tim Wolf Gilberger  Is a corresponding author
  11. Michael J Blackman  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. Centre for Structural Systems Biology, Germany
  3. 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.

The following data sets were generated

Article and author information

Author details

  1. Abhinay Ramaprasad

    Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9372-5526
  2. Paul-Christian Burda

    Centre for Structural Systems Biology, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0461-4352
  3. Enrica Calvani

    Mass Spectrometry Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Aaron J Sait

    Electron Microscopy Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6091-0426
  5. Susana Alejandra Palma-Duran

    Mass Spectrometry Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Chrislaine Withers-Martinez

    Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Fiona Hackett

    Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. James Macrae

    Mass Spectrometry Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1464-8583
  9. Lucy Collinson

    Electron Microscopy Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Tim Wolf Gilberger

    Parasitology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
    For correspondence
    gilberger@bnitm.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7965-8272
  11. Michael J Blackman

    Malaria Biochemistry Laboratory, The Francis Crick Institute, London, United Kingdom
    For correspondence
    Mike.Blackman@crick.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7442-3810

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

  1. Malcolm J McConville, The University of Melbourne, Australia

Publication history

  1. Received: July 27, 2022
  2. Accepted: December 23, 2022
  3. Accepted Manuscript published: December 28, 2022 (version 1)

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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  1. Abhinay Ramaprasad
  2. Paul-Christian Burda
  3. Enrica Calvani
  4. Aaron J Sait
  5. Susana Alejandra Palma-Duran
  6. Chrislaine Withers-Martinez
  7. Fiona Hackett
  8. James Macrae
  9. Lucy Collinson
  10. Tim Wolf Gilberger
  11. Michael J Blackman
(2022)
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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