Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Post-publication record
- Nature
- Retraction
- Reason
- Duplication of/in Image;Original Data and/or Images not Provided and/or not Available;Unreliable Data;
- Date
- 3/10/2023 0:00
- Flagged by OpenAlex?
- Yes
Source: Retraction Watch, joined by DOI. OpenAlex records retraction as is_retracted, a boolean over a state space with at least four values, so it cannot express an expression of concern, a correction or a reinstatement — it reports them as false, which reads as “fine”.
Abstract
Reactive oxygen and nitrogen species (ROS and RNS) produced by the phagocytic cells are the most common arsenals used to kill the intracellular pathogens. However, Leishmania, an intracellular pathogen, has evolved mechanisms to survive by counterbalancing the toxic oxygen metabolites produced during infection. Polyamines, the major contributor in this anti-oxidant machinery, are largely dependent on the availability of L-arginine in the intracellular milieu. Argininosuccinate synthase (ASS) plays an important role as the rate-limiting step required for converting L-citrulline to argininosuccinate to provide arginine for an assortment of metabolic processes. Leishmania produce an active ASS enzyme, yet it has an incomplete urea cycle as it lacks an argininosuccinate lyase (ASL). There is no evidence for endogenous synthesis of L-arginine in Leishmania, which suggests that these parasites salvage L-arginine from extracellular milieu and makes the biological function of ASS and the production of argininosuccinate in Leishmania unclear. Our previous quantitative proteomic analysis of Leishmania promastigotes treated with sub-lethal doses of ROS, RNS, or a combination of both, led to the identification of several differentially expressed proteins which included ASS. To assess the involvement of ASS in stress management, a mutant cell line with greatly reduced ASS activity was created by a double-targeted gene replacement strategy in L. donovani promastigote. Interestingly, LdASS is encoded by three copies of allele, but Western blot analysis showed the third allele did not appear to express ASS. The free thiol levels in the mutant LdASS-/-/+ cell line were decreased. Furthermore, the cell viability in L-arginine depleted medium was greatly attenuated on exposure to different stress environments and was adversely impacted in its ability to infect mice. These findings suggest that ASS is important for Leishmania donovani to counterbalance the stressed environments encountered during infection and can be targeted for chemotherapeutic purpose to treat visceral leishmaniasis.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
The record
- Venue
- PLoS neglected tropical diseases
- Topic
- Research on Leishmaniasis Studies
- Field
- Medicine
- Canadian institutions
- McGill University
- Funders
- Central Drug Research InstituteForeign Affairs and International Trade CanadaCanadian Institutes of Health ResearchMinistry of Health and Family WelfareIndian Council of Medical ResearchGovernment of CanadaMcGill University
- Keywords
- Argininosuccinate synthaseLeishmania donovaniBiologyLeishmaniaCitrullineArgininosuccinate lyaseArginineOxidative stressIntracellularIntracellular parasiteReactive oxygen speciesPeroxiredoxinBiochemistryMicrobiologyCell biologyArginaseLeishmaniasisGeneticsVisceral leishmaniasisEnzyme
- Has abstract in OpenAlex
- yes