{"gene":"PF3D7_1034400","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2000,"finding":"SDHA (PF3D7_1034400) encodes the 620-amino-acid flavoprotein (Fp) subunit of succinate-ubiquinone oxidoreductase (complex II) in P. falciparum mitochondria; the gene is located on chromosome 10 (1860 nt ORF, predicted 69.2 kDa protein) and contains a mitochondrial presequence consistent with nuclear-encoded mitochondrial import, as well as conserved residues for substrate binding and catalysis. A P. falciparum-specific insertion and a unicellular organism-specific deletion were identified in the Fp amino acid sequence.","method":"Gene cloning, sequencing, ORF analysis, Northern blot confirmation of 3.3 kb transcript in asexual erythrocytic stages, comparative amino acid sequence analysis","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization with sequencing, transcript detection, and comparative structural analysis from a single lab; no in vitro enzymatic reconstitution or mutagenesis","pmids":["10779596"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"Disruption of pfsdha (PF3D7_1034400) in P. falciparum eliminated both succinate-ubiquinone reductase (SQR) and succinate dehydrogenase (SDH) activity of complex II, demonstrating that the SDHA flavoprotein subunit is catalytically essential for complex II activity. The loss of complex II caused growth retardation in intraerythrocytic stages, and rescue by exogenous succinate (but not fumarate) indicated that complex II functions as a quinol-fumarate reductase (QFR) — reducing fumarate to succinate — rather than as a canonical succinate dehydrogenase in intraerythrocytic parasites.","method":"Gene disruption (knockout) of pfsdha, RT-PCR and Western blot to confirm loss of Fp mRNA and protein, enzymatic assays for SQR and SDH activity, growth assays, metabolite rescue experiments (succinate vs. fumarate addition)","journal":"Parasitology international","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gene-specific knockout with multiple orthogonal readouts (enzymatic activity assay, growth phenotype, metabolite rescue), single lab but rigorous multi-method design directly linking SDHA to QFR function","pmids":["22698672"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Genetic knockout of TCA cycle enzymes in P. falciparum (including those of complex II / SDH pathway components) showed that although TCA enzyme loss did not impair asexual blood-stage growth, TCA metabolic deficiencies halted progression at later life-cycle stages. (13)C-isotope labeling of TCA mutant parasites demonstrated significant flexibility in TCA metabolism, manifesting as altered pathway fluxes and changed substrate exchange between cytosolic and mitochondrial pools.","method":"Genetic knockout (11 KO lines targeting 6 TCA enzymes), (13)C-isotope labeling mass spectrometry metabolic flux analysis, parasite growth and life-cycle stage progression assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comprehensive genetic and isotope-tracing study across multiple TCA enzymes; findings are attributed to the TCA network broadly and do not isolate SDHA specifically, single study","pmids":["25843709"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1034400 (SDHA) encodes the flavoprotein (Fp) catalytic subunit of mitochondrial complex II in P. falciparum; genetic disruption of SDHA abolishes both SQR and SDH enzymatic activities, and metabolite rescue experiments establish that in intraerythrocytic stages complex II operates as a quinol-fumarate reductase (reducing fumarate to succinate) rather than as a conventional succinate dehydrogenase, contributing to but not being absolutely essential for intraerythrocytic parasite growth."},"narrative":{"mechanistic_narrative":"PF3D7_1034400 (SDHA) encodes the 620-amino-acid flavoprotein (Fp) catalytic subunit of mitochondrial complex II (succinate-ubiquinone oxidoreductase) in Plasmodium falciparum; the protein carries a mitochondrial presequence consistent with nuclear-encoded mitochondrial import and conserved residues for substrate binding and catalysis, and the gene is transcribed in asexual erythrocytic stages [PMID:10779596]. SDHA is catalytically essential for complex II activity: disruption of pfsdha abolishes both succinate-ubiquinone reductase (SQR) and succinate dehydrogenase (SDH) activities [PMID:22698672]. Metabolite rescue after knockout establishes that in intraerythrocytic parasites complex II operates as a quinol-fumarate reductase, reducing fumarate to succinate rather than acting as a canonical succinate dehydrogenase, and its loss causes growth retardation without abolishing blood-stage viability [PMID:22698672]. Consistent with this, disruption of TCA-cycle enzymes broadly does not impair asexual blood-stage growth but halts progression at later life-cycle stages, reflecting substantial metabolic flexibility in the parasite's TCA network [PMID:25843709]. Beyond its role as the Fp subunit of complex II operating in fumarate-reductase mode, no further mechanistic detail specific to SDHA has been characterized in the available corpus.","teleology":[{"year":2000,"claim":"Before this work it was unknown whether P. falciparum encoded a flavoprotein subunit of complex II; identifying and sequencing the gene established SDHA as the nuclear-encoded, mitochondrially targeted Fp catalytic subunit expressed in asexual blood stages.","evidence":"Gene cloning, ORF/sequence analysis, Northern blot transcript detection, and comparative amino acid analysis in P. falciparum","pmids":["10779596"],"confidence":"Medium","gaps":["No in vitro enzymatic reconstitution or mutagenesis of the identified catalytic residues","Mitochondrial import and processing of the presequence not directly demonstrated","Function of the P. falciparum-specific insertion and deletion not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"It was unclear whether SDHA was required for complex II activity and in which catalytic direction the complex runs in blood stages; knockout showed the Fp subunit is essential for both SQR and SDH activity and that complex II functions as a quinol-fumarate reductase rather than a canonical succinate dehydrogenase.","evidence":"Gene disruption of pfsdha with RT-PCR/Western confirmation, enzymatic SQR and SDH assays, growth assays, and succinate-versus-fumarate metabolite rescue in P. falciparum","pmids":["22698672"],"confidence":"High","gaps":["Single lab; direction inferred from metabolite rescue rather than direct flux measurement on the isolated enzyme","Role of SDHA in non-blood (mosquito/liver) stages not addressed","No structural characterization of the assembled complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"The physiological importance of TCA metabolism, including complex II components, across the life cycle was unresolved; genetic and isotope-tracing analysis showed TCA enzymes are dispensable for asexual growth but required for later life-cycle progression, revealing broad metabolic flexibility.","evidence":"Panel of TCA-enzyme knockout lines with 13C-isotope labeling metabolic flux analysis and life-cycle stage progression assays in P. falciparum","pmids":["25843709"],"confidence":"Medium","gaps":["Findings attributed to the TCA network broadly and do not isolate SDHA specifically","Stage-specific requirement for SDHA itself not delineated","Mechanism linking flux rerouting to arrested progression not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The stage-specific requirement of SDHA across the full parasite life cycle, its assembly into complex II, and the structural basis of its fumarate-reductase directionality remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the assembled Plasmodium complex II or the Fp subunit","SDHA-specific (as opposed to network-level) contribution to transmission stages undetermined","Interaction partners within complex II not experimentally mapped in the corpus"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Mitochondrial complex II (succinate-ubiquinone oxidoreductase / quinol-fumarate reductase)"],"partners":[],"other_free_text":["SDHA is the 620-aa flavoprotein (Fp) catalytic subunit of P. falciparum complex II, with an N-terminal mitochondrial presequence and conserved substrate-binding/catalytic residues [#0].","In intraerythrocytic stages, complex II containing SDHA operates in the reverse (fumarate-reductase) direction, reducing fumarate to succinate [#1].","SDHA is catalytically required for complex II activity but not absolutely essential for asexual blood-stage growth; TCA-network loss impairs later life-cycle progression [#1, #2]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25843709","id":"PMC_25843709","title":"Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25843709","citation_count":135,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"10779596","id":"PMC_10779596","title":"Succinate dehydrogenase in Plasmodium falciparum mitochondria: molecular characterization of the SDHA and SDHB genes for the catalytic subunits, the flavoprotein (Fp) and iron-sulfur (Ip) subunits.","date":"2000","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10779596","citation_count":29,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["SDHA"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22698672","id":"PMC_22698672","title":"Toward understanding the role of mitochondrial complex II in the intraerythrocytic stages of Plasmodium falciparum: gene targeting of the Fp subunit.","date":"2012","source":"Parasitology international","url":"https://pubmed.ncbi.nlm.nih.gov/22698672","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4346,"output_tokens":1203,"usd":0.015541,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6114,"output_tokens":2374,"usd":0.04496,"stage2_stop_reason":"end_turn"},"total_usd":0.060501,"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\": 2000,\n      \"finding\": \"SDHA (PF3D7_1034400) encodes the 620-amino-acid flavoprotein (Fp) subunit of succinate-ubiquinone oxidoreductase (complex II) in P. falciparum mitochondria; the gene is located on chromosome 10 (1860 nt ORF, predicted 69.2 kDa protein) and contains a mitochondrial presequence consistent with nuclear-encoded mitochondrial import, as well as conserved residues for substrate binding and catalysis. A P. falciparum-specific insertion and a unicellular organism-specific deletion were identified in the Fp amino acid sequence.\",\n      \"method\": \"Gene cloning, sequencing, ORF analysis, Northern blot confirmation of 3.3 kb transcript in asexual erythrocytic stages, comparative amino acid sequence analysis\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization with sequencing, transcript detection, and comparative structural analysis from a single lab; no in vitro enzymatic reconstitution or mutagenesis\",\n      \"pmids\": [\"10779596\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Disruption of pfsdha (PF3D7_1034400) in P. falciparum eliminated both succinate-ubiquinone reductase (SQR) and succinate dehydrogenase (SDH) activity of complex II, demonstrating that the SDHA flavoprotein subunit is catalytically essential for complex II activity. The loss of complex II caused growth retardation in intraerythrocytic stages, and rescue by exogenous succinate (but not fumarate) indicated that complex II functions as a quinol-fumarate reductase (QFR) — reducing fumarate to succinate — rather than as a canonical succinate dehydrogenase in intraerythrocytic parasites.\",\n      \"method\": \"Gene disruption (knockout) of pfsdha, RT-PCR and Western blot to confirm loss of Fp mRNA and protein, enzymatic assays for SQR and SDH activity, growth assays, metabolite rescue experiments (succinate vs. fumarate addition)\",\n      \"journal\": \"Parasitology international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-specific knockout with multiple orthogonal readouts (enzymatic activity assay, growth phenotype, metabolite rescue), single lab but rigorous multi-method design directly linking SDHA to QFR function\",\n      \"pmids\": [\"22698672\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Genetic knockout of TCA cycle enzymes in P. falciparum (including those of complex II / SDH pathway components) showed that although TCA enzyme loss did not impair asexual blood-stage growth, TCA metabolic deficiencies halted progression at later life-cycle stages. (13)C-isotope labeling of TCA mutant parasites demonstrated significant flexibility in TCA metabolism, manifesting as altered pathway fluxes and changed substrate exchange between cytosolic and mitochondrial pools.\",\n      \"method\": \"Genetic knockout (11 KO lines targeting 6 TCA enzymes), (13)C-isotope labeling mass spectrometry metabolic flux analysis, parasite growth and life-cycle stage progression assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comprehensive genetic and isotope-tracing study across multiple TCA enzymes; findings are attributed to the TCA network broadly and do not isolate SDHA specifically, single study\",\n      \"pmids\": [\"25843709\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1034400 (SDHA) encodes the flavoprotein (Fp) catalytic subunit of mitochondrial complex II in P. falciparum; genetic disruption of SDHA abolishes both SQR and SDH enzymatic activities, and metabolite rescue experiments establish that in intraerythrocytic stages complex II operates as a quinol-fumarate reductase (reducing fumarate to succinate) rather than as a conventional succinate dehydrogenase, contributing to but not being absolutely essential for intraerythrocytic parasite growth.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PF3D7_1034400 (SDHA) encodes the 620-amino-acid flavoprotein (Fp) catalytic subunit of mitochondrial complex II (succinate-ubiquinone oxidoreductase) in Plasmodium falciparum; the protein carries a mitochondrial presequence consistent with nuclear-encoded mitochondrial import and conserved residues for substrate binding and catalysis, and the gene is transcribed in asexual erythrocytic stages [#0]. SDHA is catalytically essential for complex II activity: disruption of pfsdha abolishes both succinate-ubiquinone reductase (SQR) and succinate dehydrogenase (SDH) activities [#1]. Metabolite rescue after knockout establishes that in intraerythrocytic parasites complex II operates as a quinol-fumarate reductase, reducing fumarate to succinate rather than acting as a canonical succinate dehydrogenase, and its loss causes growth retardation without abolishing blood-stage viability [#1]. Consistent with this, disruption of TCA-cycle enzymes broadly does not impair asexual blood-stage growth but halts progression at later life-cycle stages, reflecting substantial metabolic flexibility in the parasite's TCA network [#2]. Beyond its role as the Fp subunit of complex II operating in fumarate-reductase mode, no further mechanistic detail specific to SDHA has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Before this work it was unknown whether P. falciparum encoded a flavoprotein subunit of complex II; identifying and sequencing the gene established SDHA as the nuclear-encoded, mitochondrially targeted Fp catalytic subunit expressed in asexual blood stages.\",\n      \"evidence\": \"Gene cloning, ORF/sequence analysis, Northern blot transcript detection, and comparative amino acid analysis in P. falciparum\",\n      \"pmids\": [\"10779596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro enzymatic reconstitution or mutagenesis of the identified catalytic residues\",\n        \"Mitochondrial import and processing of the presequence not directly demonstrated\",\n        \"Function of the P. falciparum-specific insertion and deletion not tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"It was unclear whether SDHA was required for complex II activity and in which catalytic direction the complex runs in blood stages; knockout showed the Fp subunit is essential for both SQR and SDH activity and that complex II functions as a quinol-fumarate reductase rather than a canonical succinate dehydrogenase.\",\n      \"evidence\": \"Gene disruption of pfsdha with RT-PCR/Western confirmation, enzymatic SQR and SDH assays, growth assays, and succinate-versus-fumarate metabolite rescue in P. falciparum\",\n      \"pmids\": [\"22698672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Single lab; direction inferred from metabolite rescue rather than direct flux measurement on the isolated enzyme\",\n        \"Role of SDHA in non-blood (mosquito/liver) stages not addressed\",\n        \"No structural characterization of the assembled complex\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The physiological importance of TCA metabolism, including complex II components, across the life cycle was unresolved; genetic and isotope-tracing analysis showed TCA enzymes are dispensable for asexual growth but required for later life-cycle progression, revealing broad metabolic flexibility.\",\n      \"evidence\": \"Panel of TCA-enzyme knockout lines with 13C-isotope labeling metabolic flux analysis and life-cycle stage progression assays in P. falciparum\",\n      \"pmids\": [\"25843709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings attributed to the TCA network broadly and do not isolate SDHA specifically\",\n        \"Stage-specific requirement for SDHA itself not delineated\",\n        \"Mechanism linking flux rerouting to arrested progression not defined\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The stage-specific requirement of SDHA across the full parasite life cycle, its assembly into complex II, and the structural basis of its fumarate-reductase directionality remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the assembled Plasmodium complex II or the Fp subunit\",\n        \"SDHA-specific (as opposed to network-level) contribution to transmission stages undetermined\",\n        \"Interaction partners within complex II not experimentally mapped in the corpus\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008177\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0000104\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0050660\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0045273\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006099\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0006105\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"Mitochondrial complex II (succinate-ubiquinone oxidoreductase / quinol-fumarate reductase)\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"SDHA is the 620-aa flavoprotein (Fp) catalytic subunit of P. falciparum complex II, with an N-terminal mitochondrial presequence and conserved substrate-binding/catalytic residues [#0].\",\n      \"In intraerythrocytic stages, complex II containing SDHA operates in the reverse (fumarate-reductase) direction, reducing fumarate to succinate [#1].\",\n      \"SDHA is catalytically required for complex II activity but not absolutely essential for asexual blood-stage growth; TCA-network loss impairs later life-cycle progression [#1, #2].\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1034400","name":null,"product":"flavoprotein subunit of succinate dehydrogenase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0518200","name":null,"product":"flavoprotein subunit of succinate dehydrogenase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0619600","name":null,"product":"flavoprotein subunit of succinate dehydrogenase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SDHA","evaluation":null}