PSS

PSS (PF3D7_1366800) is an endoplasmic reticulum-resident phosphatidylserine synthase of P. falciparum that couples phospholipid biosynthesis to inter-organelle membrane architecture during the intraerythrocytic cycle (PMID:35623558). GFP-tagging and high-resolution live microscopy place PSS at the parasite ER and in ER-protrusions that associate stably with the mitochondrial surface, forming ER-mitochondria contact sites (ERMC) that persist throughout the growth cycle and resist ER and mitochondrial stress, indicating a robustly tethered contact (PMID:35623558). Metabolically, the serine incorporated into phosphatidylserine derives mainly from degradation of host-cell hemoglobin, defining hemoglobin catabolism as the substrate input for PSS activity, and the enzyme can additionally liberate ethanolamine from PS by base exchange, feeding the ethanolamine pool for phosphatidylethanolamine synthesis (PMID:29853527). Beyond its ER/ERMC localization, its hemoglobin-derived serine input, and a single reported interaction with the phospholipid-biosynthetic enzyme CEPT (PMID:35623558), no further mechanistic detail on PSS has been characterized in the available corpus.

1. 2018 Medium

   It was unclear where the serine substrate for parasite phosphatidylserine synthesis originates; isotope tracing established that PSS draws mainly on host hemoglobin-derived serine and can also run a base-exchange reaction liberating ethanolamine, linking PSS to both PS and PE metabolism.

   Evidence Stable-isotope labeling (serine-d3, ethanolamine-d4, choline-d9) with LC/MS/MS quantification in P. falciparum

   PMID:29853527

   Open questions at the time

   • Does not identify the PF3D7_1366800 protein directly as the catalytic enzyme responsible (activity inferred from metabolic flux)
   • No enzymatic reconstitution or kinetic characterization of the purified protein
   • Relative contribution of base exchange versus other routes to the PE pool not quantified
2. 2022 Medium

   The subcellular role of PSS was unknown; GFP-tagging and live imaging localized it to the ER and ER-protrusions, and showed these protrusions form stable ER-mitochondria contact sites throughout the intraerythrocytic cycle, placing PSS at a membrane-contact interface rather than diffusely in the ER.

   Evidence GFP fusion and high-resolution live fluorescence microscopy with mitochondrial co-staining and stress assays in transgenic P. falciparum

   PMID:35623558

   Open questions at the time

   • Does not identify the molecular tether responsible for ERMC stability
   • Functional consequence of loss of PSS on contact-site formation or parasite viability not tested
   • Whether PSS catalytic activity is required for ERMC positioning is unresolved
3. 2022 Low

   Whether PSS acts alone or within a biosynthetic assembly was open; a Co-IP indicated a physical interaction with CEPT, suggesting PSS operates within an ER phospholipid-synthesis complex.

   Evidence Co-immunoprecipitation / interaction assay in P. falciparum

   PMID:35623558

   Open questions at the time

   • Single Co-IP without reciprocal pull-down described, so the interaction is not independently validated
   • Stoichiometry and directness of the PSS-CEPT association unknown
   • Functional consequence of the interaction for phospholipid flux not established

• The catalytic mechanism, structure, essentiality, and the molecular basis by which PSS-bearing ER-protrusions tether to mitochondria remain uncharacterized in the available corpus.
• No genetic knockout/knockdown phenotype for PF3D7_1366800
• No structural model or purified-enzyme kinetics
• Tether identity and regulation of ERMC unknown