{"gene":"PF3D7_0823900","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2011,"finding":"DTC (PF3D7_0823900) mediates oxoglutarate-malate, oxoglutarate-oxaloacetate, and oxoglutarate-oxoglutarate exchange across the liposome membrane, as determined by cell-free synthesis and proteoliposome reconstitution. This transport activity suggests DTC mediates oxoglutarate-malate exchange across the inner mitochondrial membrane to support the branched TCA pathway in P. falciparum.","method":"Cell-free translation followed by proteoliposome reconstitution and substrate-specificity transport assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstitution of transport activity with substrate specificity determination in a single rigorous study; no independent replication but multiple substrates tested","pmids":["21986531"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Genetic knockout of DTC (PF3D7_0823900) only mildly affects asexual blood-stage replication in P. falciparum, even in the context of additional PfMPC1/2 and YHM2 deficiency (quadruple KO), indicating DTC is dispensable for blood-stage growth under standard conditions.","method":"Genetic knockout with parasite growth assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic KO with defined cellular phenotype (growth assay), single lab, peer-reviewed publication","pmids":["40398604"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"In quadruple KO parasites lacking DTC (PF3D7_0823900), YHM2, PfMPC1, and PfMPC2, isotopic metabolite tracing showed a large decrease in glutamine-derived label in TCA cycle metabolites, indicating that DTC (together with YHM2) imports glutamine derivatives into the mitochondrion.","method":"Genetic knockout combined with isotopic metabolite tracing via HPLC-MS metabolomics","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with isotopic tracing (two orthogonal methods), single lab; attribution of glutamine import to DTC specifically is confounded by simultaneous YHM2 deletion","pmids":["40398604"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"DTC (PF3D7_0823900) is a mitochondrial inner-membrane dicarboxylate/tricarboxylate carrier in P. falciparum that catalyzes oxoglutarate-malate, oxoglutarate-oxaloacetate, and oxoglutarate-oxoglutarate exchange in vitro, and in vivo contributes—together with YHM2—to the import of glutamine-derived carbon into the mitochondrial TCA cycle during asexual blood-stage growth, though it is dispensable for parasite survival under standard conditions due to redundant carboxylic acid transport routes."},"narrative":{"mechanistic_narrative":"DTC (PF3D7_0823900) is a carboxylic acid carrier of the P. falciparum mitochondrion that supplies carbon to the parasite's branched TCA metabolism [PMID:21986531, PMID:40398604]. In vitro reconstitution of cell-free-synthesized protein into proteoliposomes established its transport activity as oxoglutarate-malate, oxoglutarate-oxaloacetate, and oxoglutarate-oxoglutarate exchange, consistent with an oxoglutarate-malate antiporter operating across the inner mitochondrial membrane [PMID:21986531]. In vivo, isotopic tracing in parasites lacking DTC together with YHM2, PfMPC1, and PfMPC2 shows a marked loss of glutamine-derived label in TCA cycle metabolites, placing DTC—acting alongside YHM2—in the route that imports glutamine-derived carbon into the mitochondrion [PMID:40398604]. Despite this metabolic contribution, genetic knockout of DTC only mildly affects asexual blood-stage replication, even in a quadruple-carrier-deficient background, indicating it is dispensable for growth under standard conditions owing to redundant carboxylic acid transport routes [PMID:40398604]. Beyond these transport and metabolic-flux findings, no further mechanistic detail—including structural basis, regulation, or stage-specific roles—has been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Establishing what substrates DTC transports was needed to assign it a biochemical function; reconstitution showed it is an oxoglutarate exchanger, implicating it in mitochondrial carboxylic acid trafficking.","evidence":"Cell-free translation, proteoliposome reconstitution, and substrate-specificity transport assays in P. falciparum","pmids":["21986531"],"confidence":"High","gaps":["No independent replication of the reconstituted activity","In vitro liposome directionality does not confirm the physiological direction of exchange in the mitochondrion","No structural model or residue-level mechanism of substrate selection"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Whether DTC is required for blood-stage survival was unknown; genetic knockout demonstrated it is dispensable even when combined with loss of other carriers, revealing functional redundancy among carboxylic acid transporters.","evidence":"Genetic knockout (including a quadruple KO with PfMPC1/2 and YHM2) and parasite growth assays in P. falciparum","pmids":["40398604"],"confidence":"Medium","gaps":["Redundant transporters accounting for dispensability are not individually mapped","Phenotype tested only under standard blood-stage conditions","Single lab; no orthogonal confirmation of the null phenotype"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"The in vivo metabolic role of DTC was undefined; isotopic tracing in carrier-deficient parasites showed loss of glutamine-derived carbon in TCA metabolites, placing DTC in the mitochondrial import of glutamine derivatives.","evidence":"Genetic knockout combined with isotopic metabolite tracing (HPLC-MS metabolomics) in P. falciparum","pmids":["40398604"],"confidence":"Medium","gaps":["Attribution to DTC specifically is confounded by simultaneous YHM2 deletion","The precise glutamine-derived metabolite transported by DTC is not resolved","Contribution of DTC relative to YHM2 to the observed flux change is not separated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How DTC's individual transport contribution is distinguished from redundant carriers, and its structural and regulatory basis, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No single-gene metabolic phenotype isolating DTC from YHM2","No structural characterization of the transporter","No data on stage-specificity beyond asexual blood stage"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["YHM2 (FUNCTIONALLY COOPERATING CARRIER IN GLUTAMINE-DERIVED CARBON IMPORT [#2])"],"other_free_text":["Dispensable for asexual blood-stage growth under standard conditions, even in a quadruple KO with YHM2, PfMPC1, and PfMPC2 [#1]","Transport activity established only by in vitro proteoliposome reconstitution; in vivo glutamine-import role inferred from a KO context that also deletes YHM2 [#0, #2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"21986531","id":"PMC_21986531","title":"Cell-free synthesis, reconstitution, and characterization of a mitochondrial dicarboxylate-tricarboxylate carrier of Plasmodium falciparum.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21986531","citation_count":28,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["dicarboxylate/tricarboxylate carrier"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"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":["DTC"],"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":["DTC"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4423,"output_tokens":941,"usd":0.013692,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5710,"output_tokens":1982,"usd":0.03905,"stage2_stop_reason":"end_turn"},"total_usd":0.052742,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"DTC (PF3D7_0823900) mediates oxoglutarate-malate, oxoglutarate-oxaloacetate, and oxoglutarate-oxoglutarate exchange across the liposome membrane, as determined by cell-free synthesis and proteoliposome reconstitution. This transport activity suggests DTC mediates oxoglutarate-malate exchange across the inner mitochondrial membrane to support the branched TCA pathway in P. falciparum.\",\n      \"method\": \"Cell-free translation followed by proteoliposome reconstitution and substrate-specificity transport assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstitution of transport activity with substrate specificity determination in a single rigorous study; no independent replication but multiple substrates tested\",\n      \"pmids\": [\"21986531\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic knockout of DTC (PF3D7_0823900) only mildly affects asexual blood-stage replication in P. falciparum, even in the context of additional PfMPC1/2 and YHM2 deficiency (quadruple KO), indicating DTC is dispensable for blood-stage growth under standard conditions.\",\n      \"method\": \"Genetic knockout with parasite growth assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic KO with defined cellular phenotype (growth assay), single lab, peer-reviewed publication\",\n      \"pmids\": [\"40398604\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In quadruple KO parasites lacking DTC (PF3D7_0823900), YHM2, PfMPC1, and PfMPC2, isotopic metabolite tracing showed a large decrease in glutamine-derived label in TCA cycle metabolites, indicating that DTC (together with YHM2) imports glutamine derivatives into the mitochondrion.\",\n      \"method\": \"Genetic knockout combined with isotopic metabolite tracing via HPLC-MS metabolomics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with isotopic tracing (two orthogonal methods), single lab; attribution of glutamine import to DTC specifically is confounded by simultaneous YHM2 deletion\",\n      \"pmids\": [\"40398604\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"DTC (PF3D7_0823900) is a mitochondrial inner-membrane dicarboxylate/tricarboxylate carrier in P. falciparum that catalyzes oxoglutarate-malate, oxoglutarate-oxaloacetate, and oxoglutarate-oxoglutarate exchange in vitro, and in vivo contributes—together with YHM2—to the import of glutamine-derived carbon into the mitochondrial TCA cycle during asexual blood-stage growth, though it is dispensable for parasite survival under standard conditions due to redundant carboxylic acid transport routes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DTC (PF3D7_0823900) is a carboxylic acid carrier of the P. falciparum mitochondrion that supplies carbon to the parasite's branched TCA metabolism [#0, #2]. In vitro reconstitution of cell-free-synthesized protein into proteoliposomes established its transport activity as oxoglutarate-malate, oxoglutarate-oxaloacetate, and oxoglutarate-oxoglutarate exchange, consistent with an oxoglutarate-malate antiporter operating across the inner mitochondrial membrane [#0]. In vivo, isotopic tracing in parasites lacking DTC together with YHM2, PfMPC1, and PfMPC2 shows a marked loss of glutamine-derived label in TCA cycle metabolites, placing DTC—acting alongside YHM2—in the route that imports glutamine-derived carbon into the mitochondrion [#2]. Despite this metabolic contribution, genetic knockout of DTC only mildly affects asexual blood-stage replication, even in a quadruple-carrier-deficient background, indicating it is dispensable for growth under standard conditions owing to redundant carboxylic acid transport routes [#1]. Beyond these transport and metabolic-flux findings, no further mechanistic detail—including structural basis, regulation, or stage-specific roles—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing what substrates DTC transports was needed to assign it a biochemical function; reconstitution showed it is an oxoglutarate exchanger, implicating it in mitochondrial carboxylic acid trafficking.\",\n      \"evidence\": \"Cell-free translation, proteoliposome reconstitution, and substrate-specificity transport assays in P. falciparum\",\n      \"pmids\": [\"21986531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No independent replication of the reconstituted activity\",\n        \"In vitro liposome directionality does not confirm the physiological direction of exchange in the mitochondrion\",\n        \"No structural model or residue-level mechanism of substrate selection\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether DTC is required for blood-stage survival was unknown; genetic knockout demonstrated it is dispensable even when combined with loss of other carriers, revealing functional redundancy among carboxylic acid transporters.\",\n      \"evidence\": \"Genetic knockout (including a quadruple KO with PfMPC1/2 and YHM2) and parasite growth assays in P. falciparum\",\n      \"pmids\": [\"40398604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Redundant transporters accounting for dispensability are not individually mapped\",\n        \"Phenotype tested only under standard blood-stage conditions\",\n        \"Single lab; no orthogonal confirmation of the null phenotype\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The in vivo metabolic role of DTC was undefined; isotopic tracing in carrier-deficient parasites showed loss of glutamine-derived carbon in TCA metabolites, placing DTC in the mitochondrial import of glutamine derivatives.\",\n      \"evidence\": \"Genetic knockout combined with isotopic metabolite tracing (HPLC-MS metabolomics) in P. falciparum\",\n      \"pmids\": [\"40398604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Attribution to DTC specifically is confounded by simultaneous YHM2 deletion\",\n        \"The precise glutamine-derived metabolite transported by DTC is not resolved\",\n        \"Contribution of DTC relative to YHM2 to the observed flux change is not separated\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DTC's individual transport contribution is distinguished from redundant carriers, and its structural and regulatory basis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No single-gene metabolic phenotype isolating DTC from YHM2\",\n        \"No structural characterization of the transporter\",\n        \"No data on stage-specificity beyond asexual blood stage\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0015367\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0015140\", \"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, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"YHM2 (functionally cooperating carrier in glutamine-derived carbon import [#2])\"],\n    \"other_free_text\": [\n      \"Dispensable for asexual blood-stage growth under standard conditions, even in a quadruple KO with YHM2, PfMPC1, and PfMPC2 [#1]\",\n      \"Transport activity established only by in vitro proteoliposome reconstitution; in vivo glutamine-import role inferred from a KO context that also deletes YHM2 [#0, #2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0823900","name":null,"product":"dicarboxylate/tricarboxylate carrier","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0706700","name":null,"product":"dicarboxylate/tricarboxylate carrier, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1317900","name":null,"product":"dicarboxylate/tricarboxylate carrier, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"DTC","evaluation":null}