{"id":"b1c0450e-7b4b-521c-8ec2-f31b6d30a0f8","stable_key":"availability:sepsecs-sec-trna-synthesis-defect:1","predicate":"can_impair_synthesis_of_when_defective","statement":"Pathogenic SEPSECS impairment can disrupt Sec-tRNA synthesis.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"source_reported: Human genetic and biochemical evidence as summarized in the supplied source; unverified synthesis.","direction":"negative","is_public":true,"mechanism_event_id":"069c670d-ddfe-55f2-99f1-42d7ddcf2967","mechanism_event_label":"Pathogenic SEPSECS impairment can disrupt Sec-tRNA synthesis.","subject":{"id":"192979cc-02fb-5913-bace-5d5ba3983f51","slug":"sepsecs","display_name":"SEPSECS / SepSecS","entity_type_key":"protein"},"object":{"id":"15ce9978-f9e2-528c-8a2f-1079154b5383","slug":"sec-trna","display_name":"Sec-tRNA[Ser]Sec","entity_type_key":"rna"},"evidence_count":2,"mechanism_event":{"id":"069c670d-ddfe-55f2-99f1-42d7ddcf2967","stable_key":"availability:sepsecs-sec-trna-synthesis-defect:1","event_type":"availability_dependent_change","label":"Pathogenic SEPSECS impairment can disrupt Sec-tRNA synthesis.","description":"Pathogenic SEPSECS impairment affecting Sec-tRNA synthesis. Rare human genetic disorders and the defined Sec-tRNA biosynthetic pathway.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"192979cc-02fb-5913-bace-5d5ba3983f51","slug":"sepsecs","display_name":"SEPSECS / SepSecS","entity_type_key":"protein"},"role":"condition_input","stoichiometry":null,"state_label":"Pathogenic SEPSECS impairment affecting Sec-tRNA synthesis.","sequence_order":0,"notes":""},{"entity":{"id":"15ce9978-f9e2-528c-8a2f-1079154b5383","slug":"sec-trna","display_name":"Sec-tRNA[Ser]Sec","entity_type_key":"rna"},"role":"affected_component","stoichiometry":null,"state_label":"Pathogenic SEPSECS impairment affecting Sec-tRNA synthesis.","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"Pathogenic SEPSECS impairment affecting Sec-tRNA synthesis.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_scope","value_text":"Rare human genetic disorders and the defined Sec-tRNA biosynthetic pathway.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"This is not ordinary selenium dietary deficiency. SEPSECS being the SLA/LP autoantigen does not make autoimmune hepatitis a selenium-deficiency disease.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"323bab09-4146-5d78-80c3-0b3d7116a1b0","evidence_kind":"source_passage","locator":"lines 23-43","start_line":23,"end_line":43,"excerpt":"Selenocysteine (Sec) is unusual because it is synthesized on its own tRNA rather than existing as a large free amino-acid pool. There is no dedicated Sec-tRNA synthetase. Instead, two biosynthetic branches converge:\n\nSerine + tRNA^[Ser]Sec\n        ↓ SerRS\nSer-tRNA^[Ser]Sec\n        ↓ PSTK\nPSer-tRNA^[Ser]Sec ────────────────────────┐\n                                           │\nSelenide + ATP                             │\n        ↓ SEPHS2                           │\nselenophosphate ───────────────────────────┤\n                                           ↓ SEPSECS\n                                   Sec-tRNA^[Ser]Sec\n                                           ↓ eEFSec\n                              ribosome reaches UGA\n                                           ↓\n                        SECIS + SECISBP2/SBP2 machinery\n                                           ↓\n                              SELENOCYSTEINE INSERTED\n\nSerRS charging tRNA^[Ser]Sec with serine is an obligatory biosynthetic step, not a mistake. SEPHS2 supplies selenophosphate, while PSTK and SEPSECS convert the serine-charged tRNA into Sec-tRNA^[Ser]Sec.","model_system":"Supplied reference; verify the primary study and experimental context.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c788c19c-884c-5233-92b1-0bd063d87741","stable_key":"deficiency","title":"Selenium deficiency: a mechanism-first reference","document_type":"user_supplied_reference","citation_label":"Supplied selenium deficiency reference","file_path":"X:\\metabolic-ledger\\source_material\\selenium-deficiency-reference.md","sha256":"a3f14bc3fa24c595dda830664523090a7b5bfa76e9dcf517f42f62212ceb767e","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","review_status":"unverified_draft","notes":"Preserved verbatim. Reported study types are source labels, not independent verification."}},{"id":"d83ee8a0-79a2-5966-9018-4697bfe7357a","evidence_kind":"source_passage","locator":"lines 541-545","start_line":541,"end_line":545,"excerpt":"SEPSECS\n\nSec-tRNA synthesis defect\n\nPontocerebellar hypoplasia spectrum","model_system":"Supplied reference; verify the primary study and experimental context.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c788c19c-884c-5233-92b1-0bd063d87741","stable_key":"deficiency","title":"Selenium deficiency: a mechanism-first reference","document_type":"user_supplied_reference","citation_label":"Supplied selenium deficiency reference","file_path":"X:\\metabolic-ledger\\source_material\\selenium-deficiency-reference.md","sha256":"a3f14bc3fa24c595dda830664523090a7b5bfa76e9dcf517f42f62212ceb767e","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","review_status":"unverified_draft","notes":"Preserved verbatim. Reported study types are source labels, not independent verification."}}],"relations":[],"conflicts":[],"corrections":[{"id":"2c57c4ac-75e2-5d18-81f0-09bcb5ededde","title":"SEPSECS uses selenium from selenophosphate, not intact selenophosphate substitution","kind":"contradiction","status":"corrected","why":"The phosphate-for-selenophosphate wording gives the wrong product. SerRS charging is an obligatory precursor step, not an aminoacylation error.","resolution":"Record phosphate elimination/selenium donation; retain the later correction of the mischarging interpretation.","created_at":"2026-09-17 07:19:34","record_type":"correction","display_label":"Correction history","record_url":"/corrections/2c57c4ac-75e2-5d18-81f0-09bcb5ededde","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1511,"end_line":1516,"papers":[{"paper_key":"palioura-2009","title":"The human SepSecS–tRNASec complex reveals mechanism of selenocysteine formation","url":"https://pubmed.ncbi.nlm.nih.gov/19608919/","doi":"10.1126/science.1173755","year":2009,"model":"Human enzyme/tRNA crystallography and biochemical assays","summary":"Selenophosphate supplies selenium rather than being incorporated intact."}]},"sides":[{"conflict_id":"2c57c4ac-75e2-5d18-81f0-09bcb5ededde","ordinal":0,"label":"Original preserved statement","revision_id":"1fa1ebde-141f-5d47-8a4f-ba87ff84a6c6","start_line":16,"end_line":18,"quote":"3. **SerRS** mischarges tRNA^[Ser]Sec with plain **serine**. Wrong amino acid, on purpose.\n4. **PSTK** phosphorylates it → **O-phosphoseryl-tRNA**.\n5. **SepSecS** swaps the phosphate for selenophosphate → **Sec-tRNA^[Ser]Sec**. (Fun aside: SepSecS is the SLA/LP autoantigen in autoimmune hepatitis. Your immune system attacking the selenium machine.)","claim_id":null,"source_key":"molecular","source_title":"Selenium: the molecular cascade","claim_ids":[]},{"conflict_id":"2c57c4ac-75e2-5d18-81f0-09bcb5ededde","ordinal":1,"label":"Original preserved statement","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":43,"end_line":43,"quote":"SerRS charging tRNA^[Ser]Sec with serine is an obligatory biosynthetic step, not a mistake. SEPHS2 supplies selenophosphate, while PSTK and SEPSECS convert the serine-charged tRNA into Sec-tRNA^[Ser]Sec.","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]},{"conflict_id":"2c57c4ac-75e2-5d18-81f0-09bcb5ededde","ordinal":2,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1511,"end_line":1516,"quote":"## SEPSECS uses selenium from selenophosphate, not intact selenophosphate substitution\n\nThe phosphate-for-selenophosphate wording gives the wrong product. SerRS charging is an obligatory precursor step, not an aminoacylation error.\n\nRecord phosphate elimination/selenium donation; retain the later correction of the mischarging interpretation.\nPrimary reference: [The human SepSecS–tRNASec complex reveals mechanism of selenocysteine formation](https://pubmed.ncbi.nlm.nih.gov/19608919/)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]},{"id":"f7f70238-a0f3-507b-9165-8a1f8992fbdd","title":"tRNA-bound amino-acid synthesis is not unique to Sec across all biology","kind":"qualification","status":"qualified","why":"Archaeal cysteine synthesis on tRNA is a direct counterexample to only one in biology.","resolution":"Restrict to human biology or remove uniqueness; later source appropriately calls Sec unusual.","created_at":"2026-09-17 07:19:34","record_type":"qualification","display_label":"Source qualification","record_url":"/corrections/f7f70238-a0f3-507b-9165-8a1f8992fbdd","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1518,"end_line":1523,"papers":[{"paper_key":"sauerwald-2005","title":"RNA-Dependent Cysteine Biosynthesis in Archaea","url":"https://pubmed.ncbi.nlm.nih.gov/15790858/","doi":"10.1126/science.1108329","year":2005,"model":"Methanocaldococcus jannaschii enzymes and Methanococcus maripaludis genetics","summary":"Archaeal Cys is synthesized on tRNA through SepRS/SepCysS."}]},"sides":[{"conflict_id":"f7f70238-a0f3-507b-9165-8a1f8992fbdd","ordinal":0,"label":"Original preserved statement","revision_id":"1fa1ebde-141f-5d47-8a4f-ba87ff84a6c6","start_line":9,"end_line":9,"quote":"Selenocysteine (Sec, U) is the **21st amino acid**, and it's the only one in biology that is *synthesized on its own tRNA*. There is no free Sec pool. There is no SecRS synthetase.","claim_id":null,"source_key":"molecular","source_title":"Selenium: the molecular cascade","claim_ids":[]},{"conflict_id":"f7f70238-a0f3-507b-9165-8a1f8992fbdd","ordinal":1,"label":"Original preserved statement","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":23,"end_line":23,"quote":"Selenocysteine (Sec) is unusual because it is synthesized on its own tRNA rather than existing as a large free amino-acid pool. There is no dedicated Sec-tRNA synthetase. Instead, two biosynthetic branches converge:","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]},{"conflict_id":"f7f70238-a0f3-507b-9165-8a1f8992fbdd","ordinal":2,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1518,"end_line":1523,"quote":"## tRNA-bound amino-acid synthesis is not unique to Sec across all biology\n\nArchaeal cysteine synthesis on tRNA is a direct counterexample to only one in biology.\n\nRestrict to human biology or remove uniqueness; later source appropriately calls Sec unusual.\nPrimary reference: [RNA-Dependent Cysteine Biosynthesis in Archaea](https://pubmed.ncbi.nlm.nih.gov/15790858/)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]}],"research":null}