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

Ghosh, S and Kundu, R and Chandana, M and Das, R and Anand, A and Beura, S and Bobde, RC and Jain, V and Prabhu, SR and Behera, PK and Mohanty, AK and Chakrapani, M and Satyamoorthy, K and Suryawanshi, AR and Dixit, A and Padmanaban, G and Nagaraj, VA (2023) Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement. In: Nature Communications, 14 (1).

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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. © 2023, The Author(s).

Item Type:	Journal Article
Publication:	Nature Communications
Publisher:	Nature Research
Additional Information:	The copyright for this article belongs to authors.
Keywords:	artemisinin; asparagine; glutamate ammonia ligase; initiation factor 2alpha; methionine sulfoximine; phosphinothricin; proteome; amino acid; artemisinin derivative; asparagine; glutamate ammonia ligase; glutamine, amino acid; degradation; emergence; enzyme activity; glufosinate; hemoglobin; life cycle analysis; mosquito, adult; animal experiment; animal model; animal tissue; antimalarial activity; antimalarial drug resistance; Article; asexual reproduction; controlled study; cytosol; enzyme activity; enzyme regulation; enzyme structure; evolutionary adaptation; female; gametocyte; in vitro study; male; molecular evolution; mouse; nonhuman; parasite viability; plasmodium (life cycle stage); Plasmodium berghei; Plasmodium falciparum; Plasmodium vivax; protein expression; protein phosphorylation; protein synthesis inhibition; sequence alignment; sequence homology; species difference; animal; genetics; human; metabolism; parasite; Plasmodium falciparum, Amino Acids; Animals; Artemisinins; Asparagine; Glutamate-Ammonia Ligase; Glutamine; Humans; Parasites; Plasmodium falciparum
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	29 Nov 2024 10:48
Last Modified:	29 Nov 2024 10:48
URI:	http://eprints.iisc.ac.in/id/eprint/85348

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