{"gene":"PF3D7_0525100","run_date":"2026-09-07T10:55:52","timeline":{"discoveries":[{"year":2023,"finding":"PF3D7_0525100 (ACS10) is the molecular target of three structurally unrelated antimalarial compounds (MMV665924, MMV019719, MMV897615), validated by allelic replacement of resistance mutations (M300I, A268D/V, F427L) and thermal proteome profiling.","method":"Whole-genome sequencing of resistant lines, allelic replacement, thermal proteome profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (resistance genetics, allelic replacement, thermal proteome profiling) in a single rigorous study confirming ACS10 as the direct target","pmids":["36927839"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"PF3D7_0525100 (ACS10) is essential for asexual blood-stage parasite growth, as demonstrated by conditional knockdown resulting in growth arrest.","method":"Conditional knockdown with growth phenotype readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional knockdown with specific growth phenotype, single lab but with additional compound susceptibility validation","pmids":["36927839"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"Inhibition of PF3D7_0525100 (ACS10) leads to a reduction in triacylglycerols and a buildup of lipid precursors, indicating that ACS10 functions in triglyceride (triacylglycerol) biosynthesis.","method":"Lipidomic profiling following ACS10 inhibition by small molecules","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — lipid profiling directly tied to ACS10 inhibition, with corroborating genetic and pharmacological evidence in the same study","pmids":["36927839"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"PF3D7_0525100 (ACS10) is a member of a P. falciparum-specific subtelomeric ACS gene family derived by duplication from a non-subtelomeric ancestral ACS gene; all ten ACS paralogs including ACS10 are transcribed in erythrocytic stages of laboratory and field isolates.","method":"Synteny and phylogenetic analysis, Southern hybridization, transcription analysis of laboratory and field isolates","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcription confirmed across isolates, evolutionary origin inferred from phylogeny and synteny; no direct functional assay for ACS10 specifically","pmids":["16860410"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]}],"current_model":"PF3D7_0525100 (ACS10) is an essential acyl-CoA synthetase in Plasmodium falciparum asexual blood stages that functions in triglyceride biosynthesis — its inhibition reduces triacylglycerol levels and causes accumulation of lipid precursors — and is the direct target of multiple structurally unrelated antimalarial compounds, as validated by allelic replacement and thermal proteome profiling."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2006,"claim":"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","pmids":["16860410"],"confidence":"Medium","gaps":["No direct enzymatic or functional assay for ACS10 specifically","Paralog redundancy versus specialization not resolved","Substrate specificity of ACS10 not determined"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2023,"claim":"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","pmids":["36927839"],"confidence":"High","gaps":["Structural basis of compound binding not defined","Whether mutations alter catalysis or only compound binding not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"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","pmids":["36927839"],"confidence":"High","gaps":["Stage-specificity of essentiality beyond asexual blood stages not addressed","Whether essentiality reflects the triacylglycerol role or another function not disentangled"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"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","pmids":["36927839"],"confidence":"High","gaps":["Specific acyl-CoA substrate(s) activated by ACS10 not identified","Subcellular site of the reaction not established","Direct enzymatic activity not reconstituted in vitro"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The direct substrate specificity, catalytic parameters, and structural basis of both catalysis and inhibitor binding for ACS10 remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["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"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["Essential for P. falciparum asexual blood-stage growth by conditional knockdown [#1]","Direct target of antimalarial compounds MMV665924, MMV019719, and MMV897615; resistance mutations M300I, A268D/V, F427L [#0]","Member of a P. falciparum-specific subtelomeric ACS gene family of ten paralogs derived from a non-subtelomeric ancestral gene; transcribed in erythrocytic stages [#3]"]}},"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","PfACS10"],"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":1024,"usd":0.013566,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5839,"output_tokens":2137,"usd":0.04131,"stage2_stop_reason":"end_turn"},"total_usd":0.054876,"stage1_batch_id":"msgbatch_01DbiymDmubkPpYvdbAu5a7V","stage2_batch_id":"msgbatch_012TbrWvMRH129T7PQ4SmvrJ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"PF3D7_0525100 (ACS10) is the molecular target of three structurally unrelated antimalarial compounds (MMV665924, MMV019719, MMV897615), validated by allelic replacement of resistance mutations (M300I, A268D/V, F427L) and thermal proteome profiling.\",\n      \"method\": \"Whole-genome sequencing of resistant lines, allelic replacement, thermal proteome profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (resistance genetics, allelic replacement, thermal proteome profiling) in a single rigorous study confirming ACS10 as the direct target\",\n      \"pmids\": [\"36927839\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PF3D7_0525100 (ACS10) is essential for asexual blood-stage parasite growth, as demonstrated by conditional knockdown resulting in growth arrest.\",\n      \"method\": \"Conditional knockdown with growth phenotype readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional knockdown with specific growth phenotype, single lab but with additional compound susceptibility validation\",\n      \"pmids\": [\"36927839\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Inhibition of PF3D7_0525100 (ACS10) leads to a reduction in triacylglycerols and a buildup of lipid precursors, indicating that ACS10 functions in triglyceride (triacylglycerol) biosynthesis.\",\n      \"method\": \"Lipidomic profiling following ACS10 inhibition by small molecules\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipid profiling directly tied to ACS10 inhibition, with corroborating genetic and pharmacological evidence in the same study\",\n      \"pmids\": [\"36927839\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PF3D7_0525100 (ACS10) is a member of a P. falciparum-specific subtelomeric ACS gene family derived by duplication from a non-subtelomeric ancestral ACS gene; all ten ACS paralogs including ACS10 are transcribed in erythrocytic stages of laboratory and field isolates.\",\n      \"method\": \"Synteny and phylogenetic analysis, Southern hybridization, transcription analysis of laboratory and field isolates\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcription confirmed across isolates, evolutionary origin inferred from phylogeny and synteny; no direct functional assay for ACS10 specifically\",\n      \"pmids\": [\"16860410\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0525100 (ACS10) is an essential acyl-CoA synthetase in Plasmodium falciparum asexual blood stages that functions in triglyceride biosynthesis — its inhibition reduces triacylglycerol levels and causes accumulation of lipid precursors — and is the direct target of multiple structurally unrelated antimalarial compounds, as validated by allelic replacement and thermal proteome profiling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0525100 (ACS10) is an acyl-CoA synthetase essential for Plasmodium falciparum asexual blood-stage growth, where it functions in triacylglycerol biosynthesis [#1, #2]. Lipidomic profiling following its inhibition shows reduced triacylglycerol levels with a buildup of lipid precursors, placing ACS10 upstream of triglyceride assembly [#2]. 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 [#0]. 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 [#3]. 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.\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Synteny and phylogenetic analysis, Southern hybridization, and transcription analysis across laboratory and field isolates\",\n      \"pmids\": [\"16860410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct enzymatic or functional assay for ACS10 specifically\",\n        \"Paralog redundancy versus specialization not resolved\",\n        \"Substrate specificity of ACS10 not determined\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Whole-genome sequencing of resistant lines, allelic replacement of resistance mutations (M300I, A268D/V, F427L), and thermal proteome profiling in P. falciparum\",\n      \"pmids\": [\"36927839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of compound binding not defined\",\n        \"Whether mutations alter catalysis or only compound binding not resolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The requirement of ACS10 for parasite viability was untested; conditional knockdown causing growth arrest established it as essential for asexual blood-stage growth.\",\n      \"evidence\": \"Conditional knockdown with growth phenotype readout in P. falciparum\",\n      \"pmids\": [\"36927839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stage-specificity of essentiality beyond asexual blood stages not addressed\",\n        \"Whether essentiality reflects the triacylglycerol role or another function not disentangled\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Lipidomic profiling following small-molecule inhibition of ACS10 in P. falciparum\",\n      \"pmids\": [\"36927839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific acyl-CoA substrate(s) activated by ACS10 not identified\",\n        \"Subcellular site of the reaction not established\",\n        \"Direct enzymatic activity not reconstituted in vitro\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct substrate specificity, catalytic parameters, and structural basis of both catalysis and inhibitor binding for ACS10 remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vitro reconstitution of ACS10 acyl-CoA synthetase activity\",\n        \"No structural model of ACS10 or of its complex with inhibitors\",\n        \"Functional distinction between ACS10 and its nine paralogs unresolved\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003987\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0019432\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Essential for P. falciparum asexual blood-stage growth by conditional knockdown [#1]\",\n      \"Direct target of antimalarial compounds MMV665924, MMV019719, and MMV897615; resistance mutations M300I, A268D/V, F427L [#0]\",\n      \"Member of a P. falciparum-specific subtelomeric ACS gene family of ten paralogs derived from a non-subtelomeric ancestral gene; transcribed in erythrocytic stages [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0525100","name":null,"product":"acyl-CoA synthetase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1239900","name":null,"product":"acyl-CoA synthetase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1007700","name":null,"product":"acyl-CoA synthetase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ACS10","evaluation":null}