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Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement

Author

Listed:
  • Sourav Ghosh

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • Rajib Kundu

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • Manjunatha Chandana

    (Institute of Life Sciences
    Kalinga Institute of Industrial Technology)

  • Rahul Das

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • Aditya Anand

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • Subhashree Beura

    (Institute of Life Sciences)

  • Ruchir Chandrakant Bobde

    (Institute of Life Sciences
    Regional Centre for Biotechnology)

  • Vishal Jain

    (Institute of Life Sciences)

  • Sowmya Ramakant Prabhu

    (Manipal Academy of Higher Education)

  • Prativa Kumari Behera

    (Ispat General Hospital)

  • Akshaya Kumar Mohanty

    (Institute of Life Sciences
    Ispat General Hospital)

  • Mahabala Chakrapani

    (Manipal Academy of Higher Education)

  • Kapaettu Satyamoorthy

    (Manipal Academy of Higher Education)

  • Amol Ratnakar Suryawanshi

    (Institute of Life Sciences)

  • Anshuman Dixit

    (Institute of Life Sciences)

  • Govindarajan Padmanaban

    (Indian Institute of Science)

  • Viswanathan Arun Nagaraj

    (Institute of Life Sciences)

Abstract

Malaria parasite lacks canonical pathways for amino acid biosynthesis and depends primarily on hemoglobin degradation and extracellular resources for amino acids. Interestingly, a putative gene for glutamine synthetase (GS) is retained despite glutamine being an abundant amino acid in human and mosquito hosts. Here we show Plasmodium GS has evolved as a unique type I enzyme with distinct structural and regulatory properties to adapt to the asexual niche. Methionine sulfoximine (MSO) and phosphinothricin (PPT) inhibit parasite GS activity. GS is localized to the parasite cytosol and abundantly expressed in all the life cycle stages. Parasite GS displays species-specific requirement in Plasmodium falciparum (Pf) having asparagine-rich proteome. Targeting PfGS affects asparagine levels and inhibits protein synthesis through eIF2α phosphorylation leading to parasite death. Exposure of artemisinin-resistant Pf parasites to MSO and PPT inhibits the emergence of viable parasites upon artemisinin treatment.

Suggested Citation

  • Sourav Ghosh & Rajib Kundu & Manjunatha Chandana & Rahul Das & Aditya Anand & Subhashree Beura & Ruchir Chandrakant Bobde & Vishal Jain & Sowmya Ramakant Prabhu & Prativa Kumari Behera & Akshaya Kumar, 2023. "Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement," Nature Communications, Nature, vol. 14(1), pages 1-27, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39670-4
    DOI: 10.1038/s41467-023-39670-4
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    References listed on IDEAS

    as
    1. Lionel Ballut & Sébastien Violot & Santosh Shivakumaraswamy & Lakshmi Prasoona Thota & Manu Sathya & Jyothirmai Kunala & Bauke W. Dijkstra & Raphaël Terreux & Richard Haser & Hemalatha Balaram & Nushi, 2015. "Active site coupling in Plasmodium falciparum GMP synthetase is triggered by domain rotation," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
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    3. Viswanathan A. Nagaraj & Dhanunjay Mukhi & Vinayagam Sathishkumar & Pradeep A. Subramani & Susanta K. Ghosh & Rajeev R. Pandey & Manjunatha C. Shetty & Govindarajan Padmanaban, 2015. "Asparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections," Nature Communications, Nature, vol. 6(1), pages 1-13, December.
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