SPT1

TgSPT1 is a serine palmitoyltransferase that catalyzes the condensation of serine and palmitoyl-CoA, the first and rate-limiting step of de novo sphingolipid biosynthesis in Toxoplasma gondii (PMID:28578314). Unlike the heterodimeric serine palmitoyltransferases of other eukaryotes, the apicomplexan enzyme functions as a homodimer localized to the endoplasmic reticulum, and phylogenetic analysis places its origin in a lateral gene transfer from prokaryotes (Sphingomonadaceae) (PMID:28578314). Genetic ablation of TgSPT1 drastically depletes ceramides and ceramide phosphoethanolamines while sparing sphingomyelins, reducing parasite growth and producing a selective defect in rhoptry discharge that manifests as accumulation of secretory vesicles and consequent invasion failure (PMID:35977499). Loss of TgSPT1 also severely reduces brain cyst burden in chronically infected mice, linking this biosynthetic step to persistence in vivo (PMID:35977499). Beyond these findings, no further mechanistic detail has been characterized in the available corpus.

1. 2017 High

   Establishing that the apicomplexan serine palmitoyltransferase catalyzes the committed step of sphingolipid biosynthesis defined the entry point of the pathway and revealed an unusual homodimeric, ER-localized architecture distinct from eukaryotic heterodimeric SPTs.

   Evidence In vitro enzymatic assay, structural analysis, subcellular localization, and phylogenetic analysis in T. gondii

   PMID:28578314

   Open questions at the time

   • No high-resolution structure of the homodimer interface reported
   • The functional consequence of the prokaryotic evolutionary origin for enzyme regulation is not addressed
   • Cellular sphingolipid output was not measured in this study
2. 2022 High

   Genetic deletion connected TgSPT1 enzymatic activity to specific lipid products and a discrete cellular phenotype, showing that de novo ceramide synthesis is required for rhoptry discharge, host cell invasion, and chronic persistence.

   Evidence Gene knockout with lipidomics, growth and invasion assays, rhoptry secretion assay, and in vivo cyst burden in mice

   PMID:35977499

   Open questions at the time

   • The mechanistic link between ceramide/CPE depletion and defective rhoptry discharge is not resolved
   • Why sphingomyelin pools are spared while ceramides and CPEs are depleted is unexplained
   • The molecular basis of reduced chronic cyst burden is not defined

• How ceramide-dependent lipid supply is coupled to rhoptry biogenesis and secretion at the molecular level remains unknown.
• No molecular intermediary linking ceramide depletion to rhoptry secretory-vesicle defect identified
• No structural model of the TgSPT1 homodimer
• Regulation of TgSPT1 activity in vivo uncharacterized