{"gene":"PF3D7_1223800","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2025,"finding":"Genetic knockout of YHM2 (PF3D7_1223800), alone or in combination with DTC and both PfMPCs (quadruple KO), only mildly affected asexual blood-stage replication in P. falciparum. Isotopic metabolite tracing (HPLC-MS) in these quadruple KO mutants revealed a large decrease in glutamine-derived label in TCA cycle metabolites, indicating that YHM2 (together with DTC) imports glutamine derivatives into the mitochondrion rather than being required for glucose-derived carbon import.","method":"Genetic knockout combined with isotopic metabolite tracing via HPLC-MS metabolomic analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined metabolic phenotype using isotopic tracing; single lab but two orthogonal methods (growth assay + metabolomics)","pmids":["40398604"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Genetic knockout of YHM2 (PF3D7_1223800), alone or combined with DTC and both PfMPCs (quadruple KO), only mildly affected asexual blood-stage replication. Isotopic metabolite tracing showed a large decrease in glutamine-derived label in TCA cycle metabolites in quadruple KO mutants, suggesting YHM2 and DTC both import glutamine derivatives into the mitochondrion.","method":"Genetic knockout combined with isotopic metabolite tracing via HPLC-MS metabolomic analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint version of the peer-reviewed finding; single lab, same methods as published paper","pmids":["39651245"],"is_preprint":true,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1223800 (YHM2) is a putative mitochondrial citrate/α-ketoglutarate carrier in P. falciparum whose genetic deletion (alone or in combination with other mitochondrial carboxylic acid transporters) only mildly impairs asexual blood-stage replication, but isotopic tracing demonstrates that YHM2 contributes to importing glutamine-derived carbon into the mitochondrion to support TCA cycle metabolism."},"narrative":{"mechanistic_narrative":"PF3D7_1223800 (YHM2) is a putative mitochondrial carboxylic acid carrier in Plasmodium falciparum that contributes to feeding glutamine-derived carbon into the mitochondrial TCA cycle during asexual blood-stage growth [PMID:40398604]. Genetic knockout of YHM2, either alone or in combination with the dicarboxylate/tricarboxylate carrier DTC and both mitochondrial pyruvate carriers (PfMPCs) as a quadruple knockout, only mildly impairs asexual replication, indicating YHM2 is not individually essential for blood-stage proliferation [PMID:40398604]. Isotopic metabolite tracing by HPLC-MS in the quadruple knockout showed a large reduction in glutamine-derived label in TCA cycle metabolites, establishing that YHM2 (together with DTC) imports glutamine derivatives into the mitochondrion rather than being required for glucose-derived carbon import [PMID:40398604]. Beyond this metabolic role, no direct biochemical demonstration of YHM2 transport activity, substrate specificity, or its subcellular localization has been characterized in the available corpus.","teleology":[{"year":2025,"claim":"It was unknown which mitochondrial carriers route glutamine-derived carbon into the P. falciparum TCA cycle; combining genetic ablation with isotopic tracing showed YHM2 contributes to this import while being dispensable for glucose-derived carbon entry, defining its metabolic role rather than an essential proliferative one.","evidence":"Genetic knockout of YHM2 alone and in a quadruple KO with DTC and both PfMPCs, combined with glutamine isotopic tracing via HPLC-MS metabolomics and blood-stage growth assays","pmids":["40398604"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of YHM2 transport activity or substrate specificity (citrate vs alpha-ketoglutarate vs glutamine derivatives)","Contributions of YHM2 versus DTC to glutamine import not resolved individually","Subcellular localization of YHM2 not experimentally confirmed in the corpus"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether YHM2 directly transports a defined substrate, and its specific contribution independent of DTC and other mitochondrial carriers, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vitro transport assay or reconstituted-liposome demonstration of substrate handling","No single-gene metabolic phenotype separating YHM2 from DTC","No structural or localization data"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["DTC (DICARBOXYLATE/TRICARBOXYLATE CARRIER) — FUNCTIONS ALONGSIDE YHM2 IN GLUTAMINE-DERIVED CARBON IMPORT [#0]"],"other_free_text":["Quadruple knockout of YHM2, DTC, and both PfMPCs only mildly impairs asexual blood-stage replication, indicating functional redundancy or non-essentiality of these carriers for proliferation [#0]","YHM2 is not required for glucose-derived carbon import into the mitochondrion [#0]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"40398604","id":"PMC_40398604","title":"Multiple, redundant carboxylic acid transporters support mitochondrial metabolism in Plasmodium falciparum.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40398604","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["YHM2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39651245","id":"PMC_39651245","title":"MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN PLASMODIUM FALCIPARUM.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39651245","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["YHM2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40676505","id":"","title":"Direct long-read visualization reveals hidden variation in GCH1 gene copy number and precise expansion steps.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40676505","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["YHM2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41009722","id":"","title":"Targeting Mitochondrial Function in Plasmodium falciparum: Insight into Antimalarial Drugs and the Emerging Role of Saccharomyces cerevisiae as a Model System.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41009722","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["YHM2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39817177","id":"","title":"Metabolic changes that allow Plasmodium falciparum artemisinin-resistant parasites to tolerate oxidative stress.","date":"2024","source":"Frontiers in parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/39817177","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["YHM2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33382691","id":"","title":"Genetic diversity of the Plasmodium falciparum GTP-cyclohydrolase 1, dihydrofolate reductase and dihydropteroate synthetase genes reveals new insights into sulfadoxine-pyrimethamine antimalarial drug resistance.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33382691","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["YHM2"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8324,"output_tokens":710,"usd":0.017811,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5366,"output_tokens":1406,"usd":0.03099,"stage2_stop_reason":"end_turn"},"total_usd":0.048801,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic knockout of YHM2 (PF3D7_1223800), alone or in combination with DTC and both PfMPCs (quadruple KO), only mildly affected asexual blood-stage replication in P. falciparum. Isotopic metabolite tracing (HPLC-MS) in these quadruple KO mutants revealed a large decrease in glutamine-derived label in TCA cycle metabolites, indicating that YHM2 (together with DTC) imports glutamine derivatives into the mitochondrion rather than being required for glucose-derived carbon import.\",\n      \"method\": \"Genetic knockout combined with isotopic metabolite tracing via HPLC-MS metabolomic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined metabolic phenotype using isotopic tracing; single lab but two orthogonal methods (growth assay + metabolomics)\",\n      \"pmids\": [\"40398604\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Genetic knockout of YHM2 (PF3D7_1223800), alone or combined with DTC and both PfMPCs (quadruple KO), only mildly affected asexual blood-stage replication. Isotopic metabolite tracing showed a large decrease in glutamine-derived label in TCA cycle metabolites in quadruple KO mutants, suggesting YHM2 and DTC both import glutamine derivatives into the mitochondrion.\",\n      \"method\": \"Genetic knockout combined with isotopic metabolite tracing via HPLC-MS metabolomic analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint version of the peer-reviewed finding; single lab, same methods as published paper\",\n      \"pmids\": [\"39651245\"],\n      \"is_preprint\": true,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1223800 (YHM2) is a putative mitochondrial citrate/α-ketoglutarate carrier in P. falciparum whose genetic deletion (alone or in combination with other mitochondrial carboxylic acid transporters) only mildly impairs asexual blood-stage replication, but isotopic tracing demonstrates that YHM2 contributes to importing glutamine-derived carbon into the mitochondrion to support TCA cycle metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1223800 (YHM2) is a putative mitochondrial carboxylic acid carrier in Plasmodium falciparum that contributes to feeding glutamine-derived carbon into the mitochondrial TCA cycle during asexual blood-stage growth [#0]. Genetic knockout of YHM2, either alone or in combination with the dicarboxylate/tricarboxylate carrier DTC and both mitochondrial pyruvate carriers (PfMPCs) as a quadruple knockout, only mildly impairs asexual replication, indicating YHM2 is not individually essential for blood-stage proliferation [#0]. Isotopic metabolite tracing by HPLC-MS in the quadruple knockout showed a large reduction in glutamine-derived label in TCA cycle metabolites, establishing that YHM2 (together with DTC) imports glutamine derivatives into the mitochondrion rather than being required for glucose-derived carbon import [#0]. Beyond this metabolic role, no direct biochemical demonstration of YHM2 transport activity, substrate specificity, or its subcellular localization has been characterized in the available corpus.\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"It was unknown which mitochondrial carriers route glutamine-derived carbon into the P. falciparum TCA cycle; combining genetic ablation with isotopic tracing showed YHM2 contributes to this import while being dispensable for glucose-derived carbon entry, defining its metabolic role rather than an essential proliferative one.\",\n      \"evidence\": \"Genetic knockout of YHM2 alone and in a quadruple KO with DTC and both PfMPCs, combined with glutamine isotopic tracing via HPLC-MS metabolomics and blood-stage growth assays\",\n      \"pmids\": [\"40398604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical reconstitution of YHM2 transport activity or substrate specificity (citrate vs alpha-ketoglutarate vs glutamine derivatives)\",\n        \"Contributions of YHM2 versus DTC to glutamine import not resolved individually\",\n        \"Subcellular localization of YHM2 not experimentally confirmed in the corpus\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether YHM2 directly transports a defined substrate, and its specific contribution independent of DTC and other mitochondrial carriers, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro transport assay or reconstituted-liposome demonstration of substrate handling\",\n        \"No single-gene metabolic phenotype separating YHM2 from DTC\",\n        \"No structural or localization data\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0015137\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006099\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DTC (dicarboxylate/tricarboxylate carrier) — functions alongside YHM2 in glutamine-derived carbon import [#0]\"\n    ],\n    \"other_free_text\": [\n      \"Quadruple knockout of YHM2, DTC, and both PfMPCs only mildly impairs asexual blood-stage replication, indicating functional redundancy or non-essentiality of these carriers for proliferation [#0]\",\n      \"YHM2 is not required for glucose-derived carbon import into the mitochondrion [#0]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1223800","name":null,"product":"citrate/oxoglutarate carrier protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1438700","name":null,"product":"citrate/oxoglutarate carrier protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1443000","name":null,"product":"citrate/oxoglutarate carrier protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"YHM2","evaluation":null}