PGM1

PGM1 (PF3D7_1120100) is an essential phosphoglycerate mutase required for intraerythrocytic survival of Plasmodium falciparum (PMID:35150741). It functions as a tetramer: the residue W68 mediates oligomerization, and its mutation to alanine abolishes tetramer formation and drastically reduces catalytic activity in vitro, while the conserved residue K100 is likewise required for enzymatic activity (PMID:35150741). Consistent with an essential metabolic role, conditional knockdown impairs parasite growth and ectopic wild-type expression enhances growth, whereas the monomeric W68 mutant confers no growth advantage (PMID:35150741). PGM1 is subject to dual control by the acetyltransferase PfGCN5: PfGCN5 acetylates the catalytic K100 residue to increase PGM1 protein stability and pool size rather than to directly alter catalytic rate, and PfGCN5 also occupies the PGM1 promoter in a stage-specific manner such that its knockdown lowers PGM1 transcript levels (PMID:40567037). Beyond these established regulatory and structural features, PGM1 has been captured in redox-proteomic screens as a target of S-glutathionylation and as a substrate of cytosolic thioredoxin 1, though no PGM1-specific functional consequence of these modifications has been characterized in the available corpus (PMID:21595565, PMID:20307687).

1. 2010 Low

   To place PGM1 within the parasite's redox network, it was asked whether the enzyme is a substrate of the thioredoxin reduction pathway.

   Evidence Trx-affinity chromatography using a cysteine-mutant (C33S) trap with LC-MS/MS identification

   PMID:20307687

   Open questions at the time

   • Single affinity pulldown/MS identification with no functional follow-up on PGM1 activity
   • Which cysteine residues are targeted is not defined
   • The physiological consequence of thioredoxin reduction of PGM1 is unknown
2. 2011 Low

   Redox-proteomic screening asked whether PGM1 undergoes reversible thiol modification, testing whether it can form a mixed disulfide with glutathione.

   Evidence Enzymatic deglutathionylation with biotin-maleimide affinity purification and proteomic mass spectrometry

   PMID:21595565

   Open questions at the time

   • Proteome-wide identification without PGM1-specific functional validation
   • Effect of S-glutathionylation on catalytic activity or tetramerization not tested
   • Modified residues not mapped
3. 2011 Low

   To determine whether the two P. falciparum PGMase-family proteins are functionally redundant, PGM1 was compared structurally and enzymatically against its paralog PfPGM2.

   Evidence Crystal structure of PfPGM2, sequence/structural comparison with PGM1, and in vitro enzymatic assays

   PMID:21689687

   Open questions at the time

   • Direct enzymatic characterization was performed on PfPGM2, not PGM1; PGM1 served only as a comparative reference
   • No structure of PGM1 itself was determined
   • The distinct catalytic conformation of PGM1 is inferred, not experimentally solved
4. 2022 High

   The central question of PGM1's essentiality and the structural basis of its activity was resolved by linking tetramerization and specific catalytic residues to enzyme function and parasite growth.

   Evidence Site-directed mutagenesis (W68A, K100) with in vitro enzymatic assays, conditional knockdown, and ectopic overexpression growth complementation

   PMID:35150741

   Open questions at the time

   • Structure of the PGM1 tetramer not solved
   • Whether K100 contributes to catalysis directly or to substrate binding is not resolved
   • Metabolic flux consequences of knockdown not quantified
5. 2025 High

   How PGM1 abundance is controlled was addressed by identifying PfGCN5 as a dual regulator acting at both the protein-stability and transcriptional levels.

   Evidence PfGCN5 knockdown with cycloheximide chase, ChIP for promoter occupancy, RT-qPCR, in vitro acetyltransferase assay, and K100 mutagenesis

   PMID:40567037

   Open questions at the time

   • Stoichiometry and dynamics of K100 acetylation in vivo not quantified
   • The deacetylase counteracting PfGCN5 on PGM1 is unidentified
   • How acetylation at the catalytic K100 stabilizes protein without altering activity is mechanistically unexplained

• It remains unknown whether the redox modifications (S-glutathionylation, thioredoxin reduction) integrate with acetylation and tetramerization to coordinately regulate PGM1 function during the parasite life cycle.
• No functional link established between redox modifications and PGM1 catalytic output
• No structural model of the PGM1 tetramer
• Cross-talk between transcriptional, acetylation, and redox control of PGM1 not tested