OAT

PF3D7_0608800 (OAT) is a pyridoxal-phosphate-dependent aminotransferase of Plasmodium falciparum that catalyzes the reversible transamination of ornithine or N-acetylornithine with alpha-ketoglutarate, and of glutamate-5-semialdehyde with glutamate and alanine, placing it within ornithine and glutamate interconversion (PMID:11704268). The enzyme shows narrow substrate specificity and is inhibited by the ornithine analogue canaline (Ki ~492 nM); isotope-tracing shows that the OAT-mediated biosynthetic route from glutamine to ornithine is quantitatively minor in the parasite (PMID:11704268). A distinctive feature of the P. falciparum enzyme is a redox-regulated activation: OAT physically interacts with thioredoxin, glutaredoxin, and plasmoredoxin, and thioredoxin enhances its activity in vitro (PMID:19360125). The 2.3 Å crystal structure identifies two active-site-loop cysteines, Cys154 and Cys163, absent from human OAT and conserved across Plasmodium, that mediate the thioredoxin interaction and drive an ~10-fold activation not seen for the human enzyme; Cys154 is additionally required for optimal enzymatic activity, consistent with a role in ornithine binding (PMID:20673832). OAT is not the genetic driver of the adaptive proline response underlying resistance to prolyl-tRNA synthetase inhibitors (PMID:41061700). Beyond these findings, the in vivo metabolic role and essentiality of PF3D7_0608800 have not been characterized in the available corpus.

1. 1993 Low

   Establishing that P. falciparum encodes a candidate ornithine aminotransferase provided the molecular starting point for characterizing amino-acid metabolism in the parasite.

   Evidence Molecular cloning and sequencing of a putative OAT gene

   PMID:8264733

   Open questions at the time

   • Abstract unavailable; enzymatic activity not demonstrated at this stage
   • No functional or localization data
2. 2001 High

   Whether the gene product was catalytically active and metabolically important was resolved by reconstituting the enzyme and measuring its reactions, inhibition, and flux contribution.

   Evidence Heterologous expression, in vitro transamination assays, substrate profiling, canaline inhibitor kinetics, and radiolabeled precursor incorporation in P. falciparum 3D7

   PMID:11704268

   Open questions at the time

   • Physiological direction of the reaction in vivo not established
   • Consequence of the low glutamine-to-ornithine flux for parasite metabolism unresolved
   • No genetic knockout of the gene
3. 2009 High

   The question of how OAT activity is regulated was addressed by identifying redoxin partners and showing thioredoxin functionally activates the enzyme.

   Evidence Active-site mutant affinity trapping with MS identification, BIAcore SPR binding verification for Trx and Grx, and in vitro activity assay

   PMID:19360125

   Open questions at the time

   • Structural basis of the Trx interaction not defined at this stage
   • Physiological significance of redox regulation in vivo not tested
4. 2010 High

   The structural and molecular basis of Plasmodium-specific redox activation was resolved, revealing parasite-unique active-site cysteines that could be targeted for selective inhibition.

   Evidence 2.3 Å X-ray crystallography, site-directed mutagenesis of Cys154 and Cys163, enzyme assays, and comparative analysis with human OAT

   PMID:20673832

   Open questions at the time

   • Redox activation demonstrated in vitro but not in living parasites
   • Whether the ~10-fold activation modulates flux under physiological conditions unknown
5. 2025 Medium

   Whether OAT mediates parasite adaptation to prolyl-tRNA synthetase inhibitors was tested and excluded, refining the pathway responsible for the adaptive proline response.

   Evidence Genetic mapping of resistance mutations, reversion of PfApiAT2 to wild type, and metabolomic proline measurement in P. falciparum

   PMID:41061700

   Open questions at the time

   • Negative result establishing non-involvement rather than a positive OAT function
   • Does not address OAT's role in other metabolic contexts

• The in vivo metabolic role, essentiality, and druggability of PF3D7_0608800 in the parasite life cycle remain to be defined.
• No knockout/conditional knockdown of OAT reported
• Subcellular localization not established
• Physiological relevance of redox activation in vivo untested