ACS10

PF3D7_0525100 (ACS10) is an acyl-CoA synthetase essential for Plasmodium falciparum asexual blood-stage growth, where it functions in triacylglycerol biosynthesis (PMID:36927839). Lipidomic profiling following its inhibition shows reduced triacylglycerol levels with a buildup of lipid precursors, placing ACS10 upstream of triglyceride assembly (PMID:36927839). ACS10 is the direct molecular target of three structurally unrelated antimalarial compounds (MMV665924, MMV019719, MMV897615), a conclusion established by whole-genome sequencing of resistant lines, allelic replacement of resistance mutations (M300I, A268D/V, F427L), and thermal proteome profiling (PMID:36927839). Evolutionarily, ACS10 is one of ten members of a P. falciparum-specific subtelomeric ACS gene family derived by duplication from a non-subtelomeric ancestral ACS gene, and is transcribed in erythrocytic stages of both laboratory and field isolates (PMID:16860410). Beyond its role in triacylglycerol biosynthesis and its identity as a druggable target, no structural model or detailed catalytic characterization of ACS10 specifically has been established in the available corpus.

1. 2006 Medium

   Before functional work, it was unknown whether ACS10 was an expressed, bona fide member of the parasite ACS repertoire; phylogenetic and transcription analysis established it as one of ten paralogs of a P. falciparum-specific subtelomeric ACS family transcribed in blood stages.

   Evidence Synteny and phylogenetic analysis, Southern hybridization, and transcription analysis across laboratory and field isolates

   PMID:16860410

   Open questions at the time

   • No direct enzymatic or functional assay for ACS10 specifically
   • Paralog redundancy versus specialization not resolved
   • Substrate specificity of ACS10 not determined
2. 2023 High

   It was unknown what target underlies the antimalarial activity of several unrelated chemotypes; resistance genetics, allelic replacement, and thermal proteome profiling converged on ACS10 as their shared direct target, establishing it as a druggable node.

   Evidence Whole-genome sequencing of resistant lines, allelic replacement of resistance mutations (M300I, A268D/V, F427L), and thermal proteome profiling in P. falciparum

   PMID:36927839

   Open questions at the time

   • Structural basis of compound binding not defined
   • Whether mutations alter catalysis or only compound binding not resolved
3. 2023 High

   The requirement of ACS10 for parasite viability was untested; conditional knockdown causing growth arrest established it as essential for asexual blood-stage growth.

   Evidence Conditional knockdown with growth phenotype readout in P. falciparum

   PMID:36927839

   Open questions at the time

   • Stage-specificity of essentiality beyond asexual blood stages not addressed
   • Whether essentiality reflects the triacylglycerol role or another function not disentangled
4. 2023 High

   The metabolic pathway served by ACS10 was unknown; lipidomic profiling after inhibition showed reduced triacylglycerols with accumulation of lipid precursors, placing ACS10 in triglyceride biosynthesis.

   Evidence Lipidomic profiling following small-molecule inhibition of ACS10 in P. falciparum

   PMID:36927839

   Open questions at the time

   • Specific acyl-CoA substrate(s) activated by ACS10 not identified
   • Subcellular site of the reaction not established
   • Direct enzymatic activity not reconstituted in vitro

• The direct substrate specificity, catalytic parameters, and structural basis of both catalysis and inhibitor binding for ACS10 remain undefined.
• No in vitro reconstitution of ACS10 acyl-CoA synthetase activity
• No structural model of ACS10 or of its complex with inhibitors
• Functional distinction between ACS10 and its nine paralogs unresolved