ArticlePLoS neglected tropical diseases2012
Leishmania donovani argininosuccinate synthase is an active enzyme associated with parasite pathogenesis.
Article in PLoS neglected tropical diseases, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 18 citations in OpenAlex.
- Ultrastructural expansion microscopy reveals unexpected levels of glycosome heterogeneity in African trypanosomes.Journal of microscopy · 2026Article
- Oxidative Stress and Survival ofExpert reviews in molecular medicine · 2025Review
- Evolutionary divergent clusters of transcribed extinct truncated retroposons drive low mRNA expression and developmental regulation in the protozoan Leishmania.BMC biology · 2024Article
- Transcriptome Analysis of Intracellular Amastigotes of ClinicalMicroorganisms · 2022Article
- Glycosome heterogeneity in kinetoplastids.Biochemical Society transactions · 2021Review
- Genomic insights into virulence mechanisms of Leishmania donovani: evidence from an atypical strain.BMC genomics · 2018Article
- Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent.Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases · 2018Article
- Genome wide comparison of Ethiopian Leishmania donovani strains reveals differences potentially related to parasite survival.PLoS genetics · 2018Article
- L-Asparaginase of Leishmania donovani: Metabolic target and its role in Amphotericin B resistance.International journal for parasitology. Drugs and drug resistance · 2017Article
- Extracellular vesicles from human liver stem cells restore argininosuccinate synthase deficiency.Stem cell research & therapy · 2017Article
- Arginine and Polyamines Fate inFrontiers in microbiology · 2017Review
- Standardized methods to generate mock (spiked) clinical specimens by spiking blood or plasma with cultured pathogens.Journal of applied microbiology · 2016Article
- Article
- Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management.PLoS neglected tropical diseases · 2016Article
- Heterogeneity of molecular resistance patterns in antimony-resistant field isolates of Leishmania species from the western Mediterranean area.Antimicrobial agents and chemotherapy · 2014Article
- Identification and characterization of genes involved in leishmania pathogenesis: the potential for drug target selection.Molecular biology international · 2011Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGene expression analysis in Leishmania donovani (Ld) identified an orthologue of the urea cycle enzyme, argininosuccinate synthase (LdASS), that was more abundantly expressed in amastigotes than in promastigotes. In order to characterize in detail this newly identified protein in Leishmania, we determined its enzymatic activity, subcellular localization in the parasite and affect on virulence in vivo. METHODOLOGY/PRINCIPAL
findingsTwo parasite cell lines either over expressing wild type LdASS or a mutant form (G128S) associated with severe cases of citrullinemia in humans were developed. In addition we also produced bacterially expressed recombinant forms of the same proteins. Our results demonstrated that LdASS has argininosuccinate synthase enzymatic activity that is abolished using an ASS specific inhibitor (MDLA: methyl-D-L-Aspartic acid). However, the mutant form of the protein is inactive. We demonstrate that though LdASS has a glycosomal targeting signal that binds the targeting apparatus in vitro, only a small proportion of the total cellular ASS is localized in a vesicle, as indicated by protection from protease digestion of the crude organelle fraction. The majority of LdASS was found to be in the cytosolic fraction that may include large cytosolic complexes as indicated by the punctate distribution in IFA. Surprisingly, comparison to known glycosomal proteins by IFA revealed that LdASS was located in a structure different from the known glycosomal vesicles. Significantly, parasites expressing a mutant form of LdASS associated with a loss of in vitro activity had reduced virulence in vivo in BALB/c mice as demonstrated by a significant reduction in the parasite load in spleen and liver. CONCLUSION/SIGNIFICANCE: Our study suggests that LdASS is an active enzyme, with unique localization and essential for parasite survival and growth in the mammalian host. Based on these observations LdASS could be further explored as a potential drug target.
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