CDS1

TgCDS1 is a eukaryotic-type CDP-diacylglycerol synthase that resides in the endoplasmic reticulum of Toxoplasma gondii and drives glycerophospholipid biogenesis by generating a CDP-DAG pool used preferentially for phosphatidylinositol synthesis in the Golgi bodies (PMID:28314772). It operates in a division-of-labor arrangement with the apicoplast-localized prokaryotic-type TgCDS2: TgCDS1-derived CDP-DAG feeds phosphatidylinositol synthesis while TgCDS2-derived CDP-DAG feeds mitochondrial phosphatidylglycerol synthesis, and the residual growth of the TgCDS1 mutant is abolished only by additional deletion of TgCDS2, establishing their functional complementarity (PMID:28314772). TgCDS1 is essential for asexual replication, as its conditional knockdown severely attenuates parasite growth and nearly eliminates virulence in mice (PMID:28314772). Beyond these findings, no further mechanistic detail on TgCDS1 catalysis, regulation, or structure has been characterized in the available corpus.

1. 2017 High

   It was unknown which enzyme generates the CDP-DAG feeding phosphatidylinositol synthesis in T. gondii; localizing TgCDS1 to the ER and linking its knockdown to a specific drop in phosphatidylinositol established it as a eukaryotic-type CDP-DAG synthase dedicated to PI biogenesis.

   Evidence Direct imaging for localization plus conditional knockdown with lipidomic profiling

   PMID:28314772

   Open questions at the time

   • No direct enzymatic reconstitution of CDP-DAG synthase activity
   • No structural model or catalytic residue mapping
   • Mechanism directing CDP-DAG preferentially toward Golgi PI synthesis unresolved
2. 2017 High

   Whether TgCDS1 is required for parasite fitness was unknown; conditional knockdown showing severe growth attenuation and near-complete loss of virulence established it as essential for asexual replication.

   Evidence Conditional knockdown with growth assay and mouse virulence model

   PMID:28314772

   Open questions at the time

   • Whether attenuation is directly attributable to phosphatidylinositol depletion versus broader lipid imbalance not fully dissected
   • Contribution to stages beyond asexual replication untested
3. 2017 High

   It was unclear how the ER and apicoplast CDP-DAG synthases partition their roles; genetic epistasis showed TgCDS1 and TgCDS2 act in a division of labor, with double deletion abolishing residual growth.

   Evidence Consecutive deletion of TgCDS2 in a TgCDS1 knockdown background with lipidomic analysis

   PMID:28314772

   Open questions at the time

   • Extent of functional overlap/redundancy between the two synthases not quantified
   • Regulation coordinating the two pools unknown

• The catalytic mechanism, structural basis, and regulation of TgCDS1, and the determinants routing its CDP-DAG product to Golgi phosphatidylinositol synthesis, remain unresolved.
• No in vitro reconstitution of enzyme activity
• No structural data
• Trafficking of CDP-DAG from ER to Golgi uncharacterized