DHHC9

DHHC9 (PF3D7_1115900) is a catalytically active palmitoyl-S-acyl transferase of Plasmodium falciparum with a stage-specific role in the parasite life cycle (PMID:27060339). In an in vitro palmitoyl-transferase activity assay, recombinant PF3D7_1115900 palmitoylated P. falciparum substrates, and because multiple DHHC enzymes could modify the same substrate, its catalytic contribution overlaps with that of other family members in vitro (PMID:27060339). In P. falciparum schizonts the enzyme localizes to distinct organelles, and while its disruption leaves asexual blood-stage growth unaffected, it significantly reduces gametocyte formation, indicating a selective requirement in gametocytogenesis rather than in asexual replication (PMID:27060339). In P. berghei, deletion of the DHHC9 ortholog produces a phenotype that is enhanced by concurrent deletion of DHHC3, revealing functional overlap between the two enzymes in gliding motility-related processes (PMID:27084458). Beyond these findings, the specific physiological substrates of PF3D7_1115900 and the molecular basis of its role in gametocytogenesis have not been characterized in the available corpus.

1. 2016 Medium

   Whether PF3D7_1115900 is enzymatically functional was addressed by testing its catalytic activity directly, establishing it as a bona fide palmitoyl-transferase rather than an inferred family member.

   Evidence In vitro palmitoyl-transferase activity assay with recombinant P. falciparum DHHC proteins and parasite substrates

   PMID:27060339

   Open questions at the time

   • No physiological substrate of PF3D7_1115900 identified in vivo
   • Redundancy in vitro leaves the enzyme's unique substrate specificity unresolved
   • Single lab, single method
2. 2016 Medium

   The cellular role of PF3D7_1115900 was defined by asking where it acts and which life-cycle stage requires it, revealing a dispensable role in asexual growth but a requirement for efficient gametocytogenesis.

   Evidence Endogenous tagging for organellar localization plus gene disruption with blood-stage growth and gametocyte formation readouts in P. falciparum schizonts

   PMID:27060339

   Open questions at the time

   • The molecular mechanism linking PF3D7_1115900 activity to gametocyte formation is unresolved
   • The specific organelles it localizes to are not molecularly identified
   • Substrates palmitoylated during gametocytogenesis are unknown
3. 2016 Low

   Whether DHHC9 acts alone or shares function with a sibling enzyme was tested genetically, showing functional overlap with DHHC3 in gliding motility-related processes in a rodent malaria model.

   Evidence Double knockout of DHHC3 and DHHC9 compared to single knockouts with in vivo phenotypic analysis in P. berghei

   PMID:27084458

   Open questions at the time

   • Genetic epistasis via double knockout in a single study; the specific molecular contribution of DHHC9 is not resolved
   • No substrate underlying the gliding motility phenotype identified
   • Relationship between the P. berghei motility role and the P. falciparum gametocyte role is untested

• The physiological substrates of PF3D7_1115900 and the mechanism by which its palmitoyl-transferase activity drives gametocytogenesis remain unknown.
• No in vivo substrate identified for PF3D7_1115900
• Structural basis of catalysis and substrate selection uncharacterized
• Mechanistic link between the enzyme and sexual-stage commitment undefined