{"gene":"TG_290980","gene_symbol":"SPT1","run_date":"2026-09-08T14:08:30","timeline":{"discoveries":[{"year":2017,"finding":"TgSPT (serine palmitoyltransferase) catalyzes the condensation of serine and palmitoyl-CoA as the first and rate-limiting step in sphingolipid biosynthesis, and unlike eukaryotic heterodimeric SPTs, the apicomplexan ortholog functions as a homodimer localized to the endoplasmic reticulum. Phylogenetic analysis indicates it was likely acquired by lateral gene transfer from prokaryotes (Sphingomonadaceae).","method":"Biochemical assay (enzymatic activity), structural analysis, subcellular localization, and phylogenetic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic activity demonstrated, structural analysis confirming homodimeric architecture, and ER localization established in a single rigorous study with multiple orthogonal methods","pmids":["28578314"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2022,"finding":"Deletion of TgSPT1 causes a drastic reduction in ceramides and ceramide phosphoethanolamines (but not sphingomyelins), decreased parasite fitness with reduced growth rates, and a selective defect in rhoptry discharge in the form of secretory vesicles, resulting in an invasion defect. TgSPT1 loss also severely reduces cyst burden in chronically infected mice.","method":"Gene deletion (knockout), lipidomics, in vitro growth assay, rhoptry secretion assay, in vivo infection model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with multiple orthogonal phenotypic readouts (lipidomics, invasion assay, rhoptry discharge, in vivo cyst burden) in a single rigorous study","pmids":["35977499"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"TgSPT1 is a homodimeric serine palmitoyltransferase localized to the endoplasmic reticulum that catalyzes the first and rate-limiting step of de novo ceramide/sphingolipid biosynthesis in T. gondii; loss of TgSPT1 depletes ceramides and ceramide phosphoethanolamines, impairs parasite growth, causes a specific defect in rhoptry secretion leading to invasion failure, and severely reduces chronic brain cyst burden."},"narrative":{"mechanistic_narrative":"TgSPT1 is a serine palmitoyltransferase that catalyzes the condensation of serine and palmitoyl-CoA, the first and rate-limiting step of de novo sphingolipid biosynthesis in Toxoplasma gondii [PMID:28578314]. Unlike the heterodimeric serine palmitoyltransferases of other eukaryotes, the apicomplexan enzyme functions as a homodimer localized to the endoplasmic reticulum, and phylogenetic analysis places its origin in a lateral gene transfer from prokaryotes (Sphingomonadaceae) [PMID:28578314]. Genetic ablation of TgSPT1 drastically depletes ceramides and ceramide phosphoethanolamines while sparing sphingomyelins, reducing parasite growth and producing a selective defect in rhoptry discharge that manifests as accumulation of secretory vesicles and consequent invasion failure [PMID:35977499]. Loss of TgSPT1 also severely reduces brain cyst burden in chronically infected mice, linking this biosynthetic step to persistence in vivo [PMID:35977499]. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2017,"claim":"Establishing that the apicomplexan serine palmitoyltransferase catalyzes the committed step of sphingolipid biosynthesis defined the entry point of the pathway and revealed an unusual homodimeric, ER-localized architecture distinct from eukaryotic heterodimeric SPTs.","evidence":"In vitro enzymatic assay, structural analysis, subcellular localization, and phylogenetic analysis in T. gondii","pmids":["28578314"],"confidence":"High","gaps":["No high-resolution structure of the homodimer interface reported","The functional consequence of the prokaryotic evolutionary origin for enzyme regulation is not addressed","Cellular sphingolipid output was not measured in this study"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2022,"claim":"Genetic deletion connected TgSPT1 enzymatic activity to specific lipid products and a discrete cellular phenotype, showing that de novo ceramide synthesis is required for rhoptry discharge, host cell invasion, and chronic persistence.","evidence":"Gene knockout with lipidomics, growth and invasion assays, rhoptry secretion assay, and in vivo cyst burden in mice","pmids":["35977499"],"confidence":"High","gaps":["The mechanistic link between ceramide/CPE depletion and defective rhoptry discharge is not resolved","Why sphingomyelin pools are spared while ceramides and CPEs are depleted is unexplained","The molecular basis of reduced chronic cyst burden is not defined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"How ceramide-dependent lipid supply is coupled to rhoptry biogenesis and secretion at the molecular level remains unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No molecular intermediary linking ceramide depletion to rhoptry secretory-vesicle defect identified","No structural model of the TgSPT1 homodimer","Regulation of TgSPT1 activity in vivo uncharacterized"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Homodimeric serine palmitoyltransferase [#0]"],"partners":[],"other_free_text":["Loss of TgSPT1 selectively impairs rhoptry discharge as secretory vesicles, causing an invasion defect [#1]","TgSPT1 deletion severely reduces brain cyst burden in chronically infected mice [#1]","Depletes ceramides and ceramide phosphoethanolamines but spares sphingomyelins [#1]","Likely acquired by lateral gene transfer from Sphingomonadaceae [#0]"]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"35977499","id":"PMC_35977499","title":"Ceramide biosynthesis is critical for establishment of the intracellular niche of Toxoplasma gondii.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35977499","citation_count":19,"is_preprint":false},{"pmid":"28578314","id":"PMC_28578314","title":"Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28578314","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3294,"output_tokens":715,"usd":0.010304,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5487,"output_tokens":1836,"usd":0.036667,"stage2_stop_reason":"end_turn"},"total_usd":0.046971,"stage1_batch_id":"msgbatch_015xmQKDRqnTh9anE4m7LiD6","stage2_batch_id":"msgbatch_01JLpkFTVhoQBNgqHCKFrVVU","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"TgSPT (serine palmitoyltransferase) catalyzes the condensation of serine and palmitoyl-CoA as the first and rate-limiting step in sphingolipid biosynthesis, and unlike eukaryotic heterodimeric SPTs, the apicomplexan ortholog functions as a homodimer localized to the endoplasmic reticulum. Phylogenetic analysis indicates it was likely acquired by lateral gene transfer from prokaryotes (Sphingomonadaceae).\",\n      \"method\": \"Biochemical assay (enzymatic activity), structural analysis, subcellular localization, and phylogenetic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic activity demonstrated, structural analysis confirming homodimeric architecture, and ER localization established in a single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"28578314\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Deletion of TgSPT1 causes a drastic reduction in ceramides and ceramide phosphoethanolamines (but not sphingomyelins), decreased parasite fitness with reduced growth rates, and a selective defect in rhoptry discharge in the form of secretory vesicles, resulting in an invasion defect. TgSPT1 loss also severely reduces cyst burden in chronically infected mice.\",\n      \"method\": \"Gene deletion (knockout), lipidomics, in vitro growth assay, rhoptry secretion assay, in vivo infection model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with multiple orthogonal phenotypic readouts (lipidomics, invasion assay, rhoptry discharge, in vivo cyst burden) in a single rigorous study\",\n      \"pmids\": [\"35977499\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"TgSPT1 is a homodimeric serine palmitoyltransferase localized to the endoplasmic reticulum that catalyzes the first and rate-limiting step of de novo ceramide/sphingolipid biosynthesis in T. gondii; loss of TgSPT1 depletes ceramides and ceramide phosphoethanolamines, impairs parasite growth, causes a specific defect in rhoptry secretion leading to invasion failure, and severely reduces chronic brain cyst burden.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TgSPT1 is a serine palmitoyltransferase that catalyzes the condensation of serine and palmitoyl-CoA, the first and rate-limiting step of de novo sphingolipid biosynthesis in Toxoplasma gondii [#0]. Unlike the heterodimeric serine palmitoyltransferases of other eukaryotes, the apicomplexan enzyme functions as a homodimer localized to the endoplasmic reticulum, and phylogenetic analysis places its origin in a lateral gene transfer from prokaryotes (Sphingomonadaceae) [#0]. Genetic ablation of TgSPT1 drastically depletes ceramides and ceramide phosphoethanolamines while sparing sphingomyelins, reducing parasite growth and producing a selective defect in rhoptry discharge that manifests as accumulation of secretory vesicles and consequent invasion failure [#1]. Loss of TgSPT1 also severely reduces brain cyst burden in chronically infected mice, linking this biosynthetic step to persistence in vivo [#1]. Beyond these findings, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing that the apicomplexan serine palmitoyltransferase catalyzes the committed step of sphingolipid biosynthesis defined the entry point of the pathway and revealed an unusual homodimeric, ER-localized architecture distinct from eukaryotic heterodimeric SPTs.\",\n      \"evidence\": \"In vitro enzymatic assay, structural analysis, subcellular localization, and phylogenetic analysis in T. gondii\",\n      \"pmids\": [\"28578314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the homodimer interface reported\",\n        \"The functional consequence of the prokaryotic evolutionary origin for enzyme regulation is not addressed\",\n        \"Cellular sphingolipid output was not measured in this study\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic deletion connected TgSPT1 enzymatic activity to specific lipid products and a discrete cellular phenotype, showing that de novo ceramide synthesis is required for rhoptry discharge, host cell invasion, and chronic persistence.\",\n      \"evidence\": \"Gene knockout with lipidomics, growth and invasion assays, rhoptry secretion assay, and in vivo cyst burden in mice\",\n      \"pmids\": [\"35977499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The mechanistic link between ceramide/CPE depletion and defective rhoptry discharge is not resolved\",\n        \"Why sphingomyelin pools are spared while ceramides and CPEs are depleted is unexplained\",\n        \"The molecular basis of reduced chronic cyst burden is not defined\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ceramide-dependent lipid supply is coupled to rhoptry biogenesis and secretion at the molecular level remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No molecular intermediary linking ceramide depletion to rhoptry secretory-vesicle defect identified\",\n        \"No structural model of the TgSPT1 homodimer\",\n        \"Regulation of TgSPT1 activity in vivo uncharacterized\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004758\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0030148\", \"supporting_discovery_ids\": [0, 1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0046513\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\"Homodimeric serine palmitoyltransferase [#0]\"],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Loss of TgSPT1 selectively impairs rhoptry discharge as secretory vesicles, causing an invasion defect [#1]\",\n      \"TgSPT1 deletion severely reduces brain cyst burden in chronically infected mice [#1]\",\n      \"Depletes ceramides and ceramide phosphoethanolamines but spares sphingomyelins [#1]\",\n      \"Likely acquired by lateral gene transfer from Sphingomonadaceae [#0]\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_290980","name":"SPT1","product":"serine palmitoyltransferase SPT1","uniprot_acc":"A0A125YFZ0","chromosome":"TGME49_chrIX","start_pos":4006799},{"strain":"GT1","gene_id":"TGGT1_290980","name":null,"product":"putative glycine C-acetyltransferase","uniprot_acc":null,"chromosome":"TGGT1_chrIX","start_pos":3815266},{"strain":"RH88","gene_id":"TGRH88_015330","name":null,"product":"putative glycine C-acetyltransferase","uniprot_acc":null,"chromosome":"CM023090","start_pos":4071299},{"strain":"VEG","gene_id":"TGVEG_290980","name":null,"product":"putative glycine C-acetyltransferase","uniprot_acc":"B9PTE5","chromosome":"TGVEG_chrIX","start_pos":4042019}]}