PRX2

TgPRX2 is a cytosolic peroxiredoxin in Toxoplasma gondii that contributes to antioxidant defence during oxidative stress (PMID:14651610). Although classified as a 1-Cys peroxiredoxin, it operates through a 2-Cys mechanism in which the active-site (peroxidatic) Cys47 forms an intermolecular disulfide with the resolving Cys209 from the C-terminal domain of a second subunit; the enzyme assembles into tetramers and hexamers but not decamers, and reduces peroxides without dependence on glutaredoxin, thioredoxin, or glutathione while also affording general antioxidant protection to substrate proteins (PMID:15694490). Functionally, TgPRX2 is not individually required for the lytic cycle under standard conditions, but acts redundantly with the cytosolic peroxidase TgPRX1, since combined deletion of both markedly impairs parasite growth (PMID:40059453).

1. 2004 Medium

   Establishing that a cytosolic Toxoplasma peroxiredoxin functions in oxidative defence answered whether the parasite deploys dedicated peroxidases against host- and self-derived oxidants.

   Evidence Overexpression under a strong promoter with H2O2 challenge and subcellular localization in T. gondii

   PMID:14651610

   Open questions at the time

   • Overexpression phenotype does not establish the endogenous requirement for the gene
   • The catalytic mechanism and physiological electron donor were not defined
2. 2005 High

   Defining the catalytic residues resolved the paradox of a 1-Cys-classified enzyme by showing it uses a 2-Cys intermolecular disulfide mechanism and clarified its oligomeric state and independence from canonical thiol donors.

   Evidence Site-directed mutagenesis of Cys47/Cys209, gel filtration, in vitro peroxidase and glutamine synthetase protection assays, and molecular modeling

   PMID:15694490

   Open questions at the time

   • The physiological reductant that recycles the disulfide was not identified
   • In vitro assays do not establish the in vivo substrate spectrum
3. 2025 Medium

   Genetic knockout answered whether TgPRX2 is essential, revealing dispensability alone but functional redundancy with TgPRX1 in supporting parasite growth.

   Evidence Single and double deletion mutants with lytic cycle/growth and H2O2 susceptibility assays in T. gondii

   PMID:40059453

   Open questions at the time

   • Molecular basis of redundancy (shared substrates vs. parallel pathways) not resolved
   • Growth impairment not linked to a specific oxidative or metabolic defect
4. 2025 Low

   Pharmacological perturbation of lipid peroxide defence linked TgPRX2 expression to redox homeostasis during induced oxidative stress.

   Evidence RSL3 (GPX4 inhibitor) treatment with transcriptomics and ROS measurement in extracellular tachyzoites

   PMID:40667873

   Open questions at the time

   • Transcriptomic downregulation is an indirect readout and does not establish a functional role for TgPRX2 in this response
   • Causal contribution of TgPRX2 to lipid ROS control was not tested genetically

• The physiological electron donor that recycles the TgPRX2 disulfide and the mechanistic basis of its redundancy with TgPRX1 remain unresolved.
• No in vivo reductant identified
• No structural model of the active oligomer under reducing conditions
• Substrate overlap with TgPRX1 not directly mapped