{"gene":"TG_216170","gene_symbol":"NFS2","run_date":"2026-09-08T11:06:30","timeline":{"discoveries":[{"year":2021,"finding":"NFS2 (TgNFS2) functions as a cysteine desulfurase involved in the first step of the plastidic (apicoplast) SUF iron-sulfur cluster biosynthesis pathway in Toxoplasma gondii; disruption of this plastidic pathway leads to loss of the apicoplast organelle and irreversible parasite death, distinguishing it from the mitochondrial Fe-S pathway whose disruption instead triggers stress-resistance stage differentiation.","method":"Conditional mutant generation (specific mutants), phenotypic analysis, and quantitative proteomics comparing plastidic vs. mitochondrial Fe-S pathway mutants","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mutants with defined cellular phenotype (organelle loss, parasite death) and quantitative proteomics; replicated across two independent publications from the same group","pmids":["34793583"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2022,"finding":"TgNFS2 depletion (cysteine desulfurase of the plastidic SUF pathway) causes severe and irreversible impairment of intracellular parasite division and membrane homeostasis; the SUF pathway is required for apicoplast-generated fatty acid synthesis (FAS II) and for production of isoprenoid-derived precursors necessary for GPI-anchored protein targeting and parasite motility.","method":"Conditional depletion of TgNFS2 and TgSUFC (ATPase of the SUF complex), phenotypic analysis of division and membrane defects, fatty acid supplementation/host scavenging experiments, assessment of GPI-anchored protein targeting and motility","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent SUF pathway mutants (NFS2 and SUFC) with multiple orthogonal phenotypic readouts (division, membrane homeostasis, fatty acid synthesis, isoprenoid/GPI pathway, motility) in a single rigorous study","pmids":["35810787"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"TgNFS2 is the cysteine desulfurase that catalyzes the first step of the apicoplast-localized SUF iron-sulfur cluster biogenesis pathway in Toxoplasma gondii; its activity is essential for producing Fe-S cofactors that support multiple downstream apicoplast-dependent processes including fatty acid (FAS II) and isoprenoid synthesis, GPI-anchored protein targeting, and parasite motility, such that TgNFS2 loss leads to irreversible apicoplast loss and parasite death."},"narrative":{"mechanistic_narrative":"TgNFS2 is the cysteine desulfurase that catalyzes the first step of the apicoplast-localized SUF iron-sulfur cluster biogenesis pathway in Toxoplasma gondii, an organellar Fe-S synthesis route distinct from the parasite's mitochondrial pathway [PMID:34793583]. Disruption of TgNFS2 collapses this plastidic pathway, causing irreversible loss of the apicoplast and parasite death, in contrast to mitochondrial Fe-S pathway disruption, which instead triggers stress-resistance stage differentiation [PMID:34793583]. Through its production of Fe-S cofactors, TgNFS2 activity — like that of the SUF-complex ATPase TgSUFC — is required for apicoplast-generated fatty acid synthesis (FAS II) and for isoprenoid-derived precursors that support GPI-anchored protein targeting and parasite motility, so that TgNFS2 depletion severely and irreversibly impairs intracellular division and membrane homeostasis [PMID:35810787]. No mechanistic detail beyond these two studies has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Establishing whether the apicoplast SUF pathway is functionally separable from the mitochondrial Fe-S pathway resolved which organellar route is indispensable for parasite survival, identifying TgNFS2 as the cysteine desulfurase initiating apicoplast Fe-S biogenesis.","evidence":"Conditional mutants with phenotypic analysis and quantitative proteomics comparing plastidic vs. mitochondrial Fe-S pathway mutants in Toxoplasma gondii","pmids":["34793583"],"confidence":"High","gaps":["No in vitro reconstitution of TgNFS2 cysteine desulfurase enzymatic activity or sulfur-transfer partners","Direct Fe-S cluster substrates/acceptors of the SUF pathway not enumerated","Structural basis of desulfurase function not resolved"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2022,"claim":"Mapping the downstream consequences of SUF pathway loss connected TgNFS2 desulfurase activity to specific apicoplast-dependent metabolic outputs, explaining why its depletion is lethal.","evidence":"Conditional depletion of TgNFS2 and TgSUFC with phenotypic readouts of division and membrane homeostasis, fatty acid supplementation/scavenging, GPI-anchored protein targeting, and motility assays in Toxoplasma gondii","pmids":["35810787"],"confidence":"High","gaps":["Which specific Fe-S apoproteins fail to mature is not directly assigned","The causal chain from Fe-S deficiency to isoprenoid and GPI defects is inferred from phenotype rather than biochemically traced"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"The biochemical mechanism of TgNFS2 — its catalytic sulfur-transfer partners, direct Fe-S cluster acceptors, and structural organization within the SUF complex — remains uncharacterized.","evidence":"","pmids":[],"confidence":"High","gaps":["No enzymatic reconstitution or kinetic characterization","No structural model of TgNFS2 or the SUF assembly complex","Full inventory of dependent Fe-S client proteins undefined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["SUF iron-sulfur cluster biogenesis complex (with TgSUFC)"],"partners":["TGSUFC"],"other_free_text":["Required for apicoplast fatty acid synthesis (FAS II) [#1]","Required for isoprenoid precursor production supporting GPI-anchored protein targeting and parasite motility [#1]","Loss causes irreversible apicoplast organelle loss and parasite death [#0]","Functionally distinct from the mitochondrial Fe-S pathway, whose disruption instead triggers stress-resistance stage differentiation [#0]"]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"34793583","id":"PMC_34793583","title":"Differential contribution of two organelles of endosymbiotic origin to iron-sulfur cluster synthesis and overall fitness in Toxoplasma.","date":"2021","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/34793583","citation_count":26,"is_preprint":false},{"pmid":"35810787","id":"PMC_35810787","title":"Disrupting the plastidic iron-sulfur cluster biogenesis pathway in Toxoplasma gondii has pleiotropic effects irreversibly impacting parasite viability.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35810787","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3343,"output_tokens":778,"usd":0.010849,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5582,"output_tokens":1842,"usd":0.03698,"stage2_stop_reason":"end_turn"},"total_usd":0.047829,"stage1_batch_id":"msgbatch_01WokvBYTB6JLnYrpD4rXnyV","stage2_batch_id":"msgbatch_01M7hsQDvz6AqVC9DLVjQzzc","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"NFS2 (TgNFS2) functions as a cysteine desulfurase involved in the first step of the plastidic (apicoplast) SUF iron-sulfur cluster biosynthesis pathway in Toxoplasma gondii; disruption of this plastidic pathway leads to loss of the apicoplast organelle and irreversible parasite death, distinguishing it from the mitochondrial Fe-S pathway whose disruption instead triggers stress-resistance stage differentiation.\",\n      \"method\": \"Conditional mutant generation (specific mutants), phenotypic analysis, and quantitative proteomics comparing plastidic vs. mitochondrial Fe-S pathway mutants\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mutants with defined cellular phenotype (organelle loss, parasite death) and quantitative proteomics; replicated across two independent publications from the same group\",\n      \"pmids\": [\"34793583\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TgNFS2 depletion (cysteine desulfurase of the plastidic SUF pathway) causes severe and irreversible impairment of intracellular parasite division and membrane homeostasis; the SUF pathway is required for apicoplast-generated fatty acid synthesis (FAS II) and for production of isoprenoid-derived precursors necessary for GPI-anchored protein targeting and parasite motility.\",\n      \"method\": \"Conditional depletion of TgNFS2 and TgSUFC (ATPase of the SUF complex), phenotypic analysis of division and membrane defects, fatty acid supplementation/host scavenging experiments, assessment of GPI-anchored protein targeting and motility\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent SUF pathway mutants (NFS2 and SUFC) with multiple orthogonal phenotypic readouts (division, membrane homeostasis, fatty acid synthesis, isoprenoid/GPI pathway, motility) in a single rigorous study\",\n      \"pmids\": [\"35810787\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"TgNFS2 is the cysteine desulfurase that catalyzes the first step of the apicoplast-localized SUF iron-sulfur cluster biogenesis pathway in Toxoplasma gondii; its activity is essential for producing Fe-S cofactors that support multiple downstream apicoplast-dependent processes including fatty acid (FAS II) and isoprenoid synthesis, GPI-anchored protein targeting, and parasite motility, such that TgNFS2 loss leads to irreversible apicoplast loss and parasite death.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TgNFS2 is the cysteine desulfurase that catalyzes the first step of the apicoplast-localized SUF iron-sulfur cluster biogenesis pathway in Toxoplasma gondii, an organellar Fe-S synthesis route distinct from the parasite's mitochondrial pathway [#0]. Disruption of TgNFS2 collapses this plastidic pathway, causing irreversible loss of the apicoplast and parasite death, in contrast to mitochondrial Fe-S pathway disruption, which instead triggers stress-resistance stage differentiation [#0]. Through its production of Fe-S cofactors, TgNFS2 activity — like that of the SUF-complex ATPase TgSUFC — is required for apicoplast-generated fatty acid synthesis (FAS II) and for isoprenoid-derived precursors that support GPI-anchored protein targeting and parasite motility, so that TgNFS2 depletion severely and irreversibly impairs intracellular division and membrane homeostasis [#1]. No mechanistic detail beyond these two studies has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing whether the apicoplast SUF pathway is functionally separable from the mitochondrial Fe-S pathway resolved which organellar route is indispensable for parasite survival, identifying TgNFS2 as the cysteine desulfurase initiating apicoplast Fe-S biogenesis.\",\n      \"evidence\": \"Conditional mutants with phenotypic analysis and quantitative proteomics comparing plastidic vs. mitochondrial Fe-S pathway mutants in Toxoplasma gondii\",\n      \"pmids\": [\"34793583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vitro reconstitution of TgNFS2 cysteine desulfurase enzymatic activity or sulfur-transfer partners\",\n        \"Direct Fe-S cluster substrates/acceptors of the SUF pathway not enumerated\",\n        \"Structural basis of desulfurase function not resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping the downstream consequences of SUF pathway loss connected TgNFS2 desulfurase activity to specific apicoplast-dependent metabolic outputs, explaining why its depletion is lethal.\",\n      \"evidence\": \"Conditional depletion of TgNFS2 and TgSUFC with phenotypic readouts of division and membrane homeostasis, fatty acid supplementation/scavenging, GPI-anchored protein targeting, and motility assays in Toxoplasma gondii\",\n      \"pmids\": [\"35810787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific Fe-S apoproteins fail to mature is not directly assigned\",\n        \"The causal chain from Fe-S deficiency to isoprenoid and GPI defects is inferred from phenotype rather than biochemically traced\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism of TgNFS2 — its catalytic sulfur-transfer partners, direct Fe-S cluster acceptors, and structural organization within the SUF complex — remains uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No enzymatic reconstitution or kinetic characterization\",\n        \"No structural model of TgNFS2 or the SUF assembly complex\",\n        \"Full inventory of dependent Fe-S client proteins undefined\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0031071\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020011\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016226\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\"SUF iron-sulfur cluster biogenesis complex (with TgSUFC)\"],\n    \"partners\": [\"TgSUFC\"],\n    \"other_free_text\": [\n      \"Required for apicoplast fatty acid synthesis (FAS II) [#1]\",\n      \"Required for isoprenoid precursor production supporting GPI-anchored protein targeting and parasite motility [#1]\",\n      \"Loss causes irreversible apicoplast organelle loss and parasite death [#0]\",\n      \"Functionally distinct from the mitochondrial Fe-S pathway, whose disruption instead triggers stress-resistance stage differentiation [#0]\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_216170","name":"NFS2","product":"cysteine desulfurase NFS2","uniprot_acc":"A0A125YTW2","chromosome":"TGME49_chrXI","start_pos":6364217},{"strain":"GT1","gene_id":"TGGT1_216170","name":null,"product":"SufS subfamily cysteine desulfurase","uniprot_acc":null,"chromosome":"TGGT1_chrXI","start_pos":6284357},{"strain":"RH88","gene_id":"TGRH88_056400","name":null,"product":"SufS subfamily cysteine desulfurase","uniprot_acc":null,"chromosome":"CM023092","start_pos":6423416},{"strain":"VEG","gene_id":"TGVEG_216170","name":null,"product":"SufS subfamily cysteine desulfurase","uniprot_acc":"A0A125YTW4","chromosome":"TGVEG_chrXI","start_pos":6358748}]}