{"gene":"PF3D7_1454500","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2021,"finding":"P. falciparum ISCU (PfIscU) functions as the iron-sulfur cluster scaffold protein in the mitochondrion. Recombinant PfIscU directly assembled [4Fe-4S] clusters without prior [2Fe-2S] formation (in contrast to homologs in other organisms). Small angle X-ray scattering and spectral studies showed PfIscU exists as a trimer and binds one [4Fe-4S] cluster. PfIscU formed a complex with the cysteine desulfurase components PfIscS and PfIsd11; unlike the canonical dimer-based desulfurase in other organisms, the P. falciparum complex assembled around a PfIscS tetramer, yielding a symmetric hetero-hexamer [2×(2PfIscS–2PfIsd11–2PfIscU)]. PfIscU directly transferred [4Fe-4S] to apo-aconitase B, bypassing the need for intermediary conversion proteins.","method":"In vitro reconstitution of [Fe-S] cluster assembly, small angle X-ray scattering (SAXS), UV-visible spectroscopy, active-site biochemistry with recombinant proteins, direct [4Fe-4S] transfer assay to apo-aconitase B","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple orthogonal methods (SAXS, spectroscopy, cluster-transfer assay) in a single rigorous study","pmids":["34032321"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"P. falciparum ISCU (PfIscU) is targeted to the mitochondrion, as confirmed by mitochondrial targeting experiments with ISC pathway proteins.","method":"Mitochondrial targeting/localization assay (immunofluorescence or organelle fractionation, as stated in the abstract as 'confirmed mitochondrial targeting')","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment in a single study; specific method not fully detailed in abstract","pmids":["34032321"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"P. falciparum ISCU (PfIscU) is a mitochondrially targeted iron-sulfur cluster scaffold protein that, as a trimer, assembles [4Fe-4S] clusters directly (bypassing the [2Fe-2S] intermediate seen in other organisms) within a structurally unusual hetero-hexameric complex with the cysteine desulfurase PfIscS and accessory subunit PfIsd11, and can directly transfer [4Fe-4S] clusters to client apoproteins such as aconitase B without requiring intermediary carrier proteins."},"narrative":{"mechanistic_narrative":"PF3D7_1454500 (ISCU) is the mitochondrial iron-sulfur cluster scaffold protein of the P. falciparum ISC pathway, providing the platform on which nascent [Fe-S] clusters are assembled before delivery to client apoproteins [PMID:34032321]. In P. falciparum, recombinant ISCU assembles a [4Fe-4S] cluster directly, without passing through a [2Fe-2S] intermediate as seen in homologs of other organisms, and exists as a trimer that binds one [4Fe-4S] cluster [PMID:34032321]. It operates within a structurally atypical hetero-hexameric machine built around a PfIscS tetramer, [2×(2PfIscS–2PfIsd11–2PfIscU)], rather than the canonical desulfurase dimer [PMID:34032321]. Once assembled, ISCU transfers its [4Fe-4S] cluster directly to apo-aconitase B, bypassing the intermediary carrier proteins required in other systems [PMID:34032321]. Beyond this single reconstitution study, no further mechanistic detail on PF3D7_1454500 has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"It was unknown how P. falciparum builds its mitochondrial iron-sulfur clusters; in vitro reconstitution established ISCU as the scaffold that assembles [4Fe-4S] directly and, unusually, bypasses the [2Fe-2S] intermediate used by homologs elsewhere.","evidence":"in vitro [Fe-S] reconstitution, UV-visible spectroscopy, SAXS, and active-site biochemistry with recombinant PfIscU","pmids":["34032321"],"confidence":"High","gaps":["The physiological role and essentiality of ISCU in living parasites was not tested","The mechanism by which direct [4Fe-4S] assembly is achieved without a [2Fe-2S] intermediate is not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"The architecture of the P. falciparum desulfurase-scaffold assembly was unknown; SAXS and complex reconstitution showed ISCU is a trimer that joins PfIscS and PfIsd11 in a symmetric hetero-hexamer organized around a PfIscS tetramer, distinct from the canonical dimer-based complex.","evidence":"SAXS and in vitro complex assembly with recombinant PfIscU, PfIscS, and PfIsd11","pmids":["34032321"],"confidence":"High","gaps":["No atomic-resolution structure of the hetero-hexamer","Functional consequence of the atypical tetrameric architecture for cluster assembly efficiency not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"Whether an assembled cluster requires intermediary carriers for delivery was unknown; a direct transfer assay showed ISCU hands its [4Fe-4S] cluster straight to apo-aconitase B, establishing carrier-independent client maturation.","evidence":"direct [4Fe-4S] cluster-transfer assay to apo-aconitase B in vitro","pmids":["34032321"],"confidence":"High","gaps":["Whether other client apoproteins are matured directly or need carriers is untested","Kinetics and specificity of transfer to physiological clients unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"claim":"The subcellular site of action was addressed by targeting experiments confirming ISCU localizes to the mitochondrion, consistent with its role in the mitochondrial ISC pathway.","evidence":"mitochondrial targeting/localization assay for ISC pathway proteins","pmids":["34032321"],"confidence":"Medium","gaps":["Specific localization method not detailed in the source","Localization dynamics across the parasite life cycle not examined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether ISCU is essential for parasite viability and how its assembly cycle is regulated in vivo remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic knockdown/knockout of PF3D7_1454500 in parasites","No in vivo validation of the hetero-hexameric complex or client transfer"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Hetero-hexameric cysteine desulfurase-scaffold complex [2×(2PfIscS–2PfIsd11–2PfIscU)] assembled around a PfIscS tetramer [#0]","PfIscU homotrimer binding one [4Fe-4S] cluster [#0]"],"partners":["PFISCS (CYSTEINE DESULFURASE) [#0]","PFISD11 (ACCESSORY SUBUNIT) [#0]","APO-ACONITASE B (CLIENT ACCEPTOR OF [4FE-4S]) [#0]"],"other_free_text":["In P. falciparum, ISCU assembles [4Fe-4S] directly without a [2Fe-2S] intermediate, unlike homologs in other organisms [#0]","ISCU transfers [4Fe-4S] to client apoproteins without intermediary carrier proteins [#0]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"34032321","id":"PMC_34032321","title":"[Fe-S] biogenesis and unusual assembly of the ISC scaffold complex in the Plasmodium falciparum mitochondrion.","date":"2021","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34032321","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfISCU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41805883","id":"","title":"Fifty shades of iron: Unorthodox mechanisms of iron acquisition and utilization in blood-stage Plasmodium parasites.","date":"2026","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/41805883","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ISCU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42113902","id":"","title":"A bacterial-type cardiolipin synthase in Plasmodium spp. supports mitochondrial respiration and is important for liver stage maturation.","date":"2026","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/42113902","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ISCU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38660623","id":"","title":"Molecular mechanisms of mitochondria-mediated ferroptosis: a potential target for antimalarial interventions.","date":"2024","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38660623","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ISCU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34656823","id":"","title":"Mitochondrial iron-sulfur clusters: Structure, function, and an emerging role in vascular biology.","date":"2021","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/34656823","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ISCU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20657648","id":"","title":"Genome wide linkage study, using a 250K SNP map, of Plasmodium falciparum infection and mild malaria attack in a Senegalese population.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20657648","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ISCU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8933,"output_tokens":833,"usd":0.019647,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5525,"output_tokens":2269,"usd":0.042175,"stage2_stop_reason":"end_turn"},"total_usd":0.061822,"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\": 2021,\n      \"finding\": \"P. falciparum ISCU (PfIscU) functions as the iron-sulfur cluster scaffold protein in the mitochondrion. Recombinant PfIscU directly assembled [4Fe-4S] clusters without prior [2Fe-2S] formation (in contrast to homologs in other organisms). Small angle X-ray scattering and spectral studies showed PfIscU exists as a trimer and binds one [4Fe-4S] cluster. PfIscU formed a complex with the cysteine desulfurase components PfIscS and PfIsd11; unlike the canonical dimer-based desulfurase in other organisms, the P. falciparum complex assembled around a PfIscS tetramer, yielding a symmetric hetero-hexamer [2×(2PfIscS–2PfIsd11–2PfIscU)]. PfIscU directly transferred [4Fe-4S] to apo-aconitase B, bypassing the need for intermediary conversion proteins.\",\n      \"method\": \"In vitro reconstitution of [Fe-S] cluster assembly, small angle X-ray scattering (SAXS), UV-visible spectroscopy, active-site biochemistry with recombinant proteins, direct [4Fe-4S] transfer assay to apo-aconitase B\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple orthogonal methods (SAXS, spectroscopy, cluster-transfer assay) in a single rigorous study\",\n      \"pmids\": [\"34032321\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"P. falciparum ISCU (PfIscU) is targeted to the mitochondrion, as confirmed by mitochondrial targeting experiments with ISC pathway proteins.\",\n      \"method\": \"Mitochondrial targeting/localization assay (immunofluorescence or organelle fractionation, as stated in the abstract as 'confirmed mitochondrial targeting')\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment in a single study; specific method not fully detailed in abstract\",\n      \"pmids\": [\"34032321\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"P. falciparum ISCU (PfIscU) is a mitochondrially targeted iron-sulfur cluster scaffold protein that, as a trimer, assembles [4Fe-4S] clusters directly (bypassing the [2Fe-2S] intermediate seen in other organisms) within a structurally unusual hetero-hexameric complex with the cysteine desulfurase PfIscS and accessory subunit PfIsd11, and can directly transfer [4Fe-4S] clusters to client apoproteins such as aconitase B without requiring intermediary carrier proteins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1454500 (ISCU) is the mitochondrial iron-sulfur cluster scaffold protein of the P. falciparum ISC pathway, providing the platform on which nascent [Fe-S] clusters are assembled before delivery to client apoproteins [#0, #1]. In P. falciparum, recombinant ISCU assembles a [4Fe-4S] cluster directly, without passing through a [2Fe-2S] intermediate as seen in homologs of other organisms, and exists as a trimer that binds one [4Fe-4S] cluster [#0]. It operates within a structurally atypical hetero-hexameric machine built around a PfIscS tetramer, [2\\u00d7(2PfIscS\\u20132PfIsd11\\u20132PfIscU)], rather than the canonical desulfurase dimer [#0]. Once assembled, ISCU transfers its [4Fe-4S] cluster directly to apo-aconitase B, bypassing the intermediary carrier proteins required in other systems [#0]. Beyond this single reconstitution study, no further mechanistic detail on PF3D7_1454500 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"It was unknown how P. falciparum builds its mitochondrial iron-sulfur clusters; in vitro reconstitution established ISCU as the scaffold that assembles [4Fe-4S] directly and, unusually, bypasses the [2Fe-2S] intermediate used by homologs elsewhere.\",\n      \"evidence\": \"in vitro [Fe-S] reconstitution, UV-visible spectroscopy, SAXS, and active-site biochemistry with recombinant PfIscU\",\n      \"pmids\": [\"34032321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The physiological role and essentiality of ISCU in living parasites was not tested\", \"The mechanism by which direct [4Fe-4S] assembly is achieved without a [2Fe-2S] intermediate is not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The architecture of the P. falciparum desulfurase-scaffold assembly was unknown; SAXS and complex reconstitution showed ISCU is a trimer that joins PfIscS and PfIsd11 in a symmetric hetero-hexamer organized around a PfIscS tetramer, distinct from the canonical dimer-based complex.\",\n      \"evidence\": \"SAXS and in vitro complex assembly with recombinant PfIscU, PfIscS, and PfIsd11\",\n      \"pmids\": [\"34032321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of the hetero-hexamer\", \"Functional consequence of the atypical tetrameric architecture for cluster assembly efficiency not addressed\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether an assembled cluster requires intermediary carriers for delivery was unknown; a direct transfer assay showed ISCU hands its [4Fe-4S] cluster straight to apo-aconitase B, establishing carrier-independent client maturation.\",\n      \"evidence\": \"direct [4Fe-4S] cluster-transfer assay to apo-aconitase B in vitro\",\n      \"pmids\": [\"34032321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other client apoproteins are matured directly or need carriers is untested\", \"Kinetics and specificity of transfer to physiological clients unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The subcellular site of action was addressed by targeting experiments confirming ISCU localizes to the mitochondrion, consistent with its role in the mitochondrial ISC pathway.\",\n      \"evidence\": \"mitochondrial targeting/localization assay for ISC pathway proteins\",\n      \"pmids\": [\"34032321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific localization method not detailed in the source\", \"Localization dynamics across the parasite life cycle not examined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ISCU is essential for parasite viability and how its assembly cycle is regulated in vivo remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genetic knockdown/knockout of PF3D7_1454500 in parasites\", \"No in vivo validation of the hetero-hexameric complex or client transfer\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051536\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016226\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0051537\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016226\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"Hetero-hexameric cysteine desulfurase-scaffold complex [2\\u00d7(2PfIscS\\u20132PfIsd11\\u20132PfIscU)] assembled around a PfIscS tetramer [#0]\",\n      \"PfIscU homotrimer binding one [4Fe-4S] cluster [#0]\"\n    ],\n    \"partners\": [\n      \"PfIscS (cysteine desulfurase) [#0]\",\n      \"PfIsd11 (accessory subunit) [#0]\",\n      \"apo-aconitase B (client acceptor of [4Fe-4S]) [#0]\"\n    ],\n    \"other_free_text\": [\n      \"In P. falciparum, ISCU assembles [4Fe-4S] directly without a [2Fe-2S] intermediate, unlike homologs in other organisms [#0]\",\n      \"ISCU transfers [4Fe-4S] to client apoproteins without intermediary carrier proteins [#0]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1454500","name":null,"product":"iron-sulfur cluster assembly protein ISCU","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1318200","name":null,"product":"iron-sulfur cluster assembly protein ISCU, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1227600","name":null,"product":"iron-sulfur cluster assembly protein ISCU, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ISCU","evaluation":null}