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

Author:

Ghosh SouravORCID,Kundu Rajib,Chandana Manjunatha,Das Rahul,Anand Aditya,Beura Subhashree,Bobde Ruchir Chandrakant,Jain Vishal,Prabhu Sowmya Ramakant,Behera Prativa Kumari,Mohanty Akshaya Kumar,Chakrapani MahabalaORCID,Satyamoorthy KapaettuORCID,Suryawanshi Amol Ratnakar,Dixit Anshuman,Padmanaban Govindarajan,Nagaraj Viswanathan ArunORCID

Abstract

AbstractMalaria 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.

Funder

DST | Science and Engineering Research Board

Intramural support from Institute of Life Sciences; ILS/17-20

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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