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

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NATURE COMMUNICATIONS
卷 14, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-023-39670-4

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The malaria parasite lacks a traditional pathway for synthesizing amino acids and relies on hemoglobin degradation and external resources for amino acids. Surprisingly, it retains a putative gene for glutamine synthetase (GS), despite glutamine being abundant in the human and mosquito hosts. This study reveals that Plasmodium GS has evolved as a unique type I enzyme with specific structural and regulatory properties suited for the asexual niche.
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 eIF2 & alpha; phosphorylation leading to parasite death. Exposure of artemisinin-resistant Pf parasites to MSO and PPT inhibits the emergence of viable parasites upon artemisinin treatment. In a study looking to examine the functional significance of glutamine synthetase (GS), the authors show that in Plasmodium, GS has evolved as a distinct type I enzyme with unique biochemical and structural features that complement the parasite niche.

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