title: Asparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections.
abstract: The proteins of Plasmodium, the malaria parasite, are strikingly rich in asparagine. Plasmodium depends primarily on host haemoglobin degradation for amino acids and has a rudimentary pathway for amino acid biosynthesis, but retains a gene encoding asparagine synthetase (AS). Here we show that deletion of AS in Plasmodium berghei (Pb) delays the asexual- and liver-stage development with substantial reduction in the formation of ookinetes, oocysts and sporozoites in mosquitoes. In the absence of asparagine synthesis, extracellular asparagine supports suboptimal survival of PbAS knockout (KO) parasites. Depletion of blood asparagine levels by treating PbASKO-infected mice with asparaginase completely prevents the development of liver stages, exflagellation of male gametocytes and the subsequent formation of sexual stages. In vivo supplementation of asparagine in mice restores the exflagellation of PbASKO parasites. Thus, the parasite life cycle has an absolute requirement for asparagine, which we propose could be targeted to prevent malaria transmission and liver infections.
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.|Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Viswanathan A
authors.initials: VA
authors.lastname: Nagaraj
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Dhanunjay
authors.initials: D
authors.lastname: Mukhi
authors.affiliation: Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Vinayagam
authors.initials: V
authors.lastname: Sathishkumar
authors.affiliation: National Institute of Malaria Research (Field Unit), Nirmal Bhawan, ICMR complex, Poojanahalli, Off NH-7, Kannamangala Post, Bangalore 562 110, India.
authors.forename: Pradeep A
authors.initials: PA
authors.lastname: Subramani
authors.affiliation: National Institute of Malaria Research (Field Unit), Nirmal Bhawan, ICMR complex, Poojanahalli, Off NH-7, Kannamangala Post, Bangalore 562 110, India.
authors.forename: Susanta K
authors.initials: SK
authors.lastname: Ghosh
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Rajeev R
authors.initials: RR
authors.lastname: Pandey
authors.affiliation: Centre for Infectious Disease Research, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Manjunatha C
authors.initials: MC
authors.lastname: Shetty
authors.affiliation: Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Padmanaban
mesh_terms: D000818:Animals; D000852:Anopheles; D001215:Asparaginase / Q000494:pharmacology; D001216:Asparagine / Q000378:metabolism* / Q000494:pharmacology; D001217:Aspartate-Ammonia Ligase / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D055786:Gene Knockout Techniques; D008018:Life Cycle Stages / Q000187:drug effects; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000469:parasitology / Q000517:prevention & control* / Q000635:transmission; D051379:Mice; D030781:Organisms, Genetically Modified; D010962:Plasmodium berghei / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001216:Asparagine; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase