{"id":"57c4fe9e-8f1d-59a1-9870-0f4cd0991267","stable_key":"a9828b14-fbd7-57bf-9e01-0d52d1b42a1f:citrulline-p5cs-low-citrulline","predicate":"associated_with_low","statement":"The two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"761206d7-465f-5c45-a785-65e634a38065","mechanism_event_label":"Low citrulline can arise from a defective upstream enzyme.","subject":{"id":"51e5ed63-8c8e-585f-b68f-025069cf63de","slug":"human-aldh18a1-r84q","display_name":"Human ALDH18A1 / P5CS R84Q variant","entity_type_key":"protein_state"},"object":{"id":"77ef287f-ecc9-5c9a-ae8b-d102f9024098","slug":"circulating-citrulline-concentration","display_name":"Circulating citrulline concentration","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"761206d7-465f-5c45-a785-65e634a38065","stable_key":"a9828b14-fbd7-57bf-9e01-0d52d1b42a1f:citrulline-p5cs-low-citrulline-event","event_type":"biochemical_relationship","label":"Low citrulline can arise from a defective upstream enzyme.","description":"The two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"39697257-d4c2-5f40-9eb1-8f230a5ac764","slug":"aldh18a1","display_name":"Human pyrroline-5-carboxylate synthase / ALDH18A1","entity_type_key":"protein"},"role":"parent_enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"f53c7bfb-3b91-56fe-bebd-28623cfe13a0","slug":"citrulline","display_name":"L-Citrulline","entity_type_key":"small_molecule"},"role":"measured_amino_acid","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c715e48e-42db-5fac-b4a4-c1285a68d085","slug":"ornithine","display_name":"L-Ornithine","entity_type_key":"small_molecule"},"role":"also_low","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"eeca3c9e-7749-5677-b7bd-37fe8f7c228d","slug":"arginine","display_name":"L-Arginine","entity_type_key":"small_molecule"},"role":"also_low","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"51e5ed63-8c8e-585f-b68f-025069cf63de","slug":"human-aldh18a1-r84q","display_name":"Human ALDH18A1 / P5CS R84Q variant","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"77ef287f-ecc9-5c9a-ae8b-d102f9024098","slug":"circulating-citrulline-concentration","display_name":"Circulating citrulline concentration","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/citrulline-research/11092761.abstract.txt\", \"locator\": \"Primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2\", \"start_char\": 0, \"end_char\": 1688, \"text_sha256\": \"09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Patient genetics and recombinant variant expression","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"ALDH18A1 R84Q compared with wild-type isoforms","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Citrulline research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"citrulline","display_name":"L-Citrulline","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"Human, two siblings and mammalian expression systems","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Low citrulline can arise from a defective upstream enzyme.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. (2000). https://pubmed.ncbi.nlm.nih.gov/11092761/ DOI: 10.1093/hmg/9.19.2853","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Mitochondrial P5CS and circulating amino acids","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"b574311a-942d-50b2-8c68-5cc54eaa32aa","evidence_kind":"source_excerpt","locator":"Lines 320-331","start_line":320,"end_line":331,"excerpt":"### citrulline-p5cs-low-citrulline\nThe two R84Q siblings had hypocitrullinemia with low ornithine, arginine and proline; the variant strongly reduced expressed P5CS activity.\nCondition category: machinery_impairment\nnutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Low citrulline can arise from a defective upstream enzyme.\norganism: Human, two siblings and mammalian expression systems\ntissue_or_cell_type: Mitochondrial P5CS and circulating amino acids\nexperimental_model: Patient genetics and recombinant variant expression\nlimitations: Rare inherited enzyme disorder; does not imply low dietary citrulline caused the clinical phenotype.\nexposure: ALDH18A1 R84Q compared with wild-type isoforms\nevidence_span: {\"source_cache\": \"artifacts/citrulline-research/11092761.abstract.txt\", \"locator\": \"Primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2\", \"start_char\": 0, \"end_char\": 1688, \"text_sha256\": \"09706fd9ec135c472473decaa612e06b3e5aa021c9b1493d77daf4fe98b8d5d2\"}\n[citrulline-p11092761] Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase. 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