ACS11

PF3D7_1238800 (ACS11) is one of ten duplicated acyl-CoA synthetase paralogs in Plasmodium falciparum that are transcribed during erythrocytic stages in both laboratory and field isolates, a gene family shaped by chromosomal recombination and diversifying (positive) selection (PMID:16860410). Functionally, ACS11 has been characterized primarily as a mediator of antimalarial resistance: specific mutations (F387V, D648Y, E668K) arise in parasite lines resistant to MMV665924, MMV019719, and MMV897615, and confer resistance by decreasing ACS11 protein stability rather than by rendering ACS11 the primary drug target (PMID:36927839). No direct enzymatic activity, substrate specificity, or acyl-CoA synthetase reaction has been established for ACS11 itself in the available corpus.

1. 2006 Low

   Establishing whether ACS11 is an expressed, evolving gene rather than a pseudogene was needed to justify functional study; showing it is transcribed in erythrocytic stages and belongs to a recombining, positively selected paralog family placed it in a biologically active gene family.

   Evidence Southern hybridization, phylogenetic and synteny analysis, transcription confirmation, and dN/dS analysis of duplicated ACS paralogs in field and lab isolates

   PMID:16860410

   Open questions at the time

   • No biochemical or functional assay specific to ACS11 protein was performed
   • Substrate specificity and enzymatic activity of ACS11 were not tested
   • Findings characterize the paralog family; ACS11-specific role remains undefined
2. 2023 Medium

   Whether ACS11 has a defined cellular role was addressed indirectly through resistance genetics; identifying stability-altering mutations that confer resistance to specific antimalarials established ACS11 as a resistance mediator distinct from the primary drug target ACS10.

   Evidence Whole-genome sequencing of resistant parasite lines, mutant allele analysis, and thermal proteome profiling interpreting F387V/D648Y/E668K as resistance mediators acting via decreased protein stability

   PMID:36927839

   Open questions at the time

   • ACS11 enzymatic activity was not reconstituted or directly assayed
   • The mechanism by which reduced ACS11 stability produces resistance is not resolved
   • The functional relationship between ACS11 and the drug target ACS10 is not directly demonstrated

• The intrinsic biochemical function of ACS11 — its acyl-CoA substrate specificity, catalytic activity, and physiological role in parasite lipid metabolism — remains uncharacterized in the available corpus.
• No demonstrated acyl-CoA synthetase activity for ACS11
• No identified substrate or product
• No subcellular localization data for ACS11 protein