{"gene":"PF3D7_1238800","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2023,"finding":"Mutations in PF3D7_1238800 (ACS11; F387V, D648Y, E668K) were identified in P. falciparum lines resistant to antimalarial compounds (MMV665924, MMV019719, MMV897615) via whole-genome sequencing; analysis of these mutations pointed to a role for ACS11 in mediating compound resistance via decreased protein stability, rather than being the primary drug target.","method":"Whole-genome sequencing of resistant parasite lines; mutant allele analysis; thermal proteome profiling (used to validate ACS10 as target, with ACS11 mutations interpreted as resistance mediators via protein stability changes)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — whole-genome sequencing plus mutant characterization in a single study; ACS11 role in resistance inferred from mutation analysis without direct functional reconstitution of ACS11 activity","pmids":["36927839"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"PF3D7_1238800 (ACS11) is one of ten duplicated ACS paralogs in P. falciparum that are transcribed during erythrocytic stages in both laboratory and field isolates; a double gene conversion event involving ACS genes on three different chromosomes of isolate 3D7 was identified and confirmed, showing that the duplicated family (including ACS11) undergoes chromosomal recombination events and is under positive (diversifying) selection based on dN/dS > 1.","method":"Southern hybridization; phylogenetic and synteny analysis; transcription confirmed in erythrocytic stages; dN/dS analysis of sequenced paralogs","journal":"Molecular and biochemical parasitology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcription and gene-family characterization in a single study; no direct biochemical or functional assay specific to ACS11 protein","pmids":["16860410"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]}],"current_model":"PF3D7_1238800 (ACS11) is a transcribed acyl-CoA synthetase paralog in P. falciparum erythrocytic stages whose specific mutations (F387V, D648Y, E668K) confer resistance to antimalarial compounds targeting the related enzyme ACS10, apparently by decreasing ACS11 protein stability rather than by directly mediating drug action; no direct enzymatic activity or substrate specificity has been established for ACS11 itself."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2006,"claim":"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","pmids":["16860410"],"confidence":"Low","gaps":["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"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2023,"claim":"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","pmids":["36927839"],"confidence":"Medium","gaps":["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"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"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.","evidence":"No direct enzymatic or substrate-mapping study of ACS11 is present in the timeline","pmids":[],"confidence":"Low","gaps":["No demonstrated acyl-CoA synthetase activity for ACS11","No identified substrate or product","No subcellular localization data for ACS11 protein"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["ACS10 (RELATED ACYL-COA SYNTHETASE; PRIMARY DRUG TARGET WITH WHICH ACS11 RESISTANCE MUTATIONS ARE FUNCTIONALLY LINKED) [#0]"],"other_free_text":["ACS11 is one of ten duplicated acyl-CoA synthetase paralogs transcribed during P. falciparum erythrocytic stages in lab and field isolates [#1].","The ACS paralog family, including ACS11, undergoes chromosomal recombination (a confirmed double gene conversion event across three chromosomes in 3D7) and is under diversifying selection (dN/dS > 1) [#1].","Mutations F387V, D648Y, and E668K in ACS11 confer resistance to MMV665924, MMV019719, and MMV897615, apparently by decreasing ACS11 protein stability rather than by direct drug interaction [#0].","No direct enzymatic activity or substrate specificity has been established for ACS11 in the available corpus."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"16860410","id":"PMC_16860410","title":"Duplication, gene conversion, and genetic diversity in the species-specific acyl-CoA synthetase gene family of Plasmodium falciparum.","date":"2006","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/16860410","citation_count":42,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["acyl-CoA synthetase"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36927839","id":"PMC_36927839","title":"Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36927839","citation_count":28,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["acyl-CoA synthetase","PfACS11"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12554091","id":"PMC_12554091","title":"The Plasmodium falciparum fatty acyl-CoA synthetase family (PfACS) and differential stage-specific expression in infected erythrocytes.","date":"2003","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/12554091","citation_count":27,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["acyl-CoA synthetase"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3924,"output_tokens":744,"usd":0.011466,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5404,"output_tokens":1669,"usd":0.034373,"stage2_stop_reason":"end_turn"},"total_usd":0.045839,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"Mutations in PF3D7_1238800 (ACS11; F387V, D648Y, E668K) were identified in P. falciparum lines resistant to antimalarial compounds (MMV665924, MMV019719, MMV897615) via whole-genome sequencing; analysis of these mutations pointed to a role for ACS11 in mediating compound resistance via decreased protein stability, rather than being the primary drug target.\",\n      \"method\": \"Whole-genome sequencing of resistant parasite lines; mutant allele analysis; thermal proteome profiling (used to validate ACS10 as target, with ACS11 mutations interpreted as resistance mediators via protein stability changes)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — whole-genome sequencing plus mutant characterization in a single study; ACS11 role in resistance inferred from mutation analysis without direct functional reconstitution of ACS11 activity\",\n      \"pmids\": [\"36927839\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PF3D7_1238800 (ACS11) is one of ten duplicated ACS paralogs in P. falciparum that are transcribed during erythrocytic stages in both laboratory and field isolates; a double gene conversion event involving ACS genes on three different chromosomes of isolate 3D7 was identified and confirmed, showing that the duplicated family (including ACS11) undergoes chromosomal recombination events and is under positive (diversifying) selection based on dN/dS > 1.\",\n      \"method\": \"Southern hybridization; phylogenetic and synteny analysis; transcription confirmed in erythrocytic stages; dN/dS analysis of sequenced paralogs\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcription and gene-family characterization in a single study; no direct biochemical or functional assay specific to ACS11 protein\",\n      \"pmids\": [\"16860410\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1238800 (ACS11) is a transcribed acyl-CoA synthetase paralog in P. falciparum erythrocytic stages whose specific mutations (F387V, D648Y, E668K) confer resistance to antimalarial compounds targeting the related enzyme ACS10, apparently by decreasing ACS11 protein stability rather than by directly mediating drug action; no direct enzymatic activity or substrate specificity has been established for ACS11 itself.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1]. 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 [#0]. No direct enzymatic activity, substrate specificity, or acyl-CoA synthetase reaction has been established for ACS11 itself in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Southern hybridization, phylogenetic and synteny analysis, transcription confirmation, and dN/dS analysis of duplicated ACS paralogs in field and lab isolates\",\n      \"pmids\": [\n        \"16860410\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical or functional assay specific to ACS11 protein was performed\",\n        \"Substrate specificity and enzymatic activity of ACS11 were not tested\",\n        \"Findings characterize the paralog family; ACS11-specific role remains undefined\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"3D7\"\n        }\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\n        \"36927839\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ACS11 enzymatic activity was not reconstituted or directly assayed\",\n        \"The mechanism by which reduced ACS11 stability produces resistance is not resolved\",\n        \"The functional relationship between ACS11 and the drug target ACS10 is not directly demonstrated\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"No direct enzymatic or substrate-mapping study of ACS11 is present in the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No demonstrated acyl-CoA synthetase activity for ACS11\",\n        \"No identified substrate or product\",\n        \"No subcellular localization data for ACS11 protein\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACS10 (related acyl-CoA synthetase; primary drug target with which ACS11 resistance mutations are functionally linked) [#0]\"\n    ],\n    \"other_free_text\": [\n      \"ACS11 is one of ten duplicated acyl-CoA synthetase paralogs transcribed during P. falciparum erythrocytic stages in lab and field isolates [#1].\",\n      \"The ACS paralog family, including ACS11, undergoes chromosomal recombination (a confirmed double gene conversion event across three chromosomes in 3D7) and is under diversifying selection (dN/dS > 1) [#1].\",\n      \"Mutations F387V, D648Y, and E668K in ACS11 confer resistance to MMV665924, MMV019719, and MMV897615, apparently by decreasing ACS11 protein stability rather than by direct drug interaction [#0].\",\n      \"No direct enzymatic activity or substrate specificity has been established for ACS11 in the available corpus.\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1238800","name":null,"product":"acyl-CoA synthetase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1453300","name":null,"product":"acyl-CoA synthetase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1458600","name":null,"product":"acyl-CoA synthetase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ACS11","evaluation":null}