{"id":"74317f8b-1c22-596f-8cbd-93088419d7b6","stable_key":"1b599eb7-b22a-5fda-bcf0-9d92b5ae1311:gb-a-metabolite-destroys-the-cofactor","predicate":"inhibits","statement":"Children with pyridoxine-dependent seizures have mutations in the ALDH7A1 gene which encodes antiquitin, these mutations abolish the activity of antiquitin as a delta-1-piperideine-6-carboxylate to alpha-aminoadipic semialdehyde dehydrogenase, the accumulating delta-1-piperideine-6-carboxylate inactivates pyridoxal 5-phosphate by forming a Knoevenagel condensation product, and measurement of urinary alpha-aminoadipic semialdehyde provides a simple way of confirming the diagnosis.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"4718bf22-83bc-5e59-9942-038e411f8091","mechanism_event_label":"A metabolite that piles up when one enzyme is missing chemically destroys the cofactor a different enzyme needs.","subject":{"id":"b758223d-7419-5da4-a5cd-0241af31631a","slug":"p6c","display_name":"Delta-1-piperideine-6-carboxylate","entity_type_key":"small_molecule"},"object":{"id":"6b656ff5-9532-5da4-8eea-8ca163a48649","slug":"pyridoxal-phosphate","display_name":"PLP","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"4718bf22-83bc-5e59-9942-038e411f8091","stable_key":"1b599eb7-b22a-5fda-bcf0-9d92b5ae1311:gb-a-metabolite-destroys-the-cofactor-event","event_type":"biochemical_relationship","label":"A metabolite that piles up when one enzyme is missing chemically destroys the cofactor a different enzyme needs.","description":"Children with pyridoxine-dependent seizures have mutations in the ALDH7A1 gene which encodes antiquitin, these mutations abolish the activity of antiquitin as a delta-1-piperideine-6-carboxylate to alpha-aminoadipic semialdehyde dehydrogenase, the accumulating delta-1-piperideine-6-carboxylate inactivates pyridoxal 5-phosphate by forming a Knoevenagel condensation product, and measurement of urinary alpha-aminoadipic semialdehyde provides a simple way of confirming the diagnosis.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e5479b92-70d9-52ec-b861-b41806db5ca4","slug":"aldh7a1","display_name":"Antiquitin / ALDH7A1","entity_type_key":"protein"},"role":"lost_enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"bab57563-35ac-58ad-b932-075afcff01cd","slug":"alpha-aasa","display_name":"Alpha-aminoadipic semialdehyde","entity_type_key":"small_molecule"},"role":"accumulating_metabolite","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"3b681a00-0971-5625-89f4-9352917f5833","slug":"plp-inactivation","display_name":"Inactivation of pyridoxal 5-phosphate by Knoevenagel condensation","entity_type_key":"cellular_process"},"role":"chemical_mechanism","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"e68a88e0-23f1-516c-831c-9df49c7ed504","slug":"pyridoxine-dependent-seizures","display_name":"Pyridoxine-dependent seizures","entity_type_key":"cellular_process"},"role":"resulting_condition","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"b758223d-7419-5da4-a5cd-0241af31631a","slug":"p6c","display_name":"Delta-1-piperideine-6-carboxylate","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"6b656ff5-9532-5da4-8eea-8ca163a48649","slug":"pyridoxal-phosphate","display_name":"PLP","entity_type_key":"small_molecule"},"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/gaba-research/16491085.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"da61b07cc71e16803fe09321738c7a6c8d2cbac0dff2b189b9f2586ce5950bfa\", \"start_char\": 0, \"end_char\": 550, \"text_sha256\": \"da61b07cc71e16803fe09321738c7a6c8d2cbac0dff2b189b9f2586ce5950bfa\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Gene analysis and metabolite measurement in children with pyridoxine-dependent seizures","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Naturally occurring ALDH7A1 mutations abolishing antiquitin dehydrogenase activity","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Human genetics with a defined biochemical consequence. It establishes the chemistry of the cofactor loss; it does not measure brain GABA in the affected children.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.","comparator":null,"unit":null,"notes":"","entity":{"slug":"gaba","display_name":"Gamma-aminobutyric acid","entity_type_key":"small_molecule"}},{"dimension":"organism","value_text":"Human","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A metabolite that piles up when one enzyme is missing chemically destroys the cofactor a different enzyme needs.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[gb-p16491085] Mutations in antiquitin in individuals with pyridoxine-dependent seizures. (2006). https://pubmed.ncbi.nlm.nih.gov/16491085/ DOI: 10.1038/nm1366","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Whole body","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":"4f7660c8-78db-59d6-93ca-5a4c7188b300","evidence_kind":"source_excerpt","locator":"Lines 118-129","start_line":118,"end_line":129,"excerpt":"### gb-a-metabolite-destroys-the-cofactor\nChildren with pyridoxine-dependent seizures have mutations in the ALDH7A1 gene which encodes antiquitin, these mutations abolish the activity of antiquitin as a delta-1-piperideine-6-carboxylate to alpha-aminoadipic semialdehyde dehydrogenase, the accumulating delta-1-piperideine-6-carboxylate inactivates pyridoxal 5-phosphate by forming a Knoevenagel condensation product, and measurement of urinary alpha-aminoadipic semialdehyde provides a simple way of confirming the diagnosis.\nCondition category: machinery_impairment\nnutrient_topic: GABA research collection; topical membership is not evidence of a direct clinical effect, and the sign of a GABA response depends on the chloride gradient of the cell it was measured in.\nplain_language: A metabolite that piles up when one enzyme is missing chemically destroys the cofactor a different enzyme needs.\norganism: Human\ntissue_or_cell_type: Whole body\nexperimental_model: Gene analysis and metabolite measurement in children with pyridoxine-dependent seizures\nlimitations: Human genetics with a defined biochemical consequence. It establishes the chemistry of the cofactor loss; it does not measure brain GABA in the affected children.\nexposure: Naturally occurring ALDH7A1 mutations abolishing antiquitin dehydrogenase activity\nevidence_span: {\"source_cache\": \"artifacts/gaba-research/16491085.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"da61b07cc71e16803fe09321738c7a6c8d2cbac0dff2b189b9f2586ce5950bfa\", \"start_char\": 0, \"end_char\": 550, \"text_sha256\": \"da61b07cc71e16803fe09321738c7a6c8d2cbac0dff2b189b9f2586ce5950bfa\"}\n[gb-p16491085] Mutations in antiquitin in individuals with pyridoxine-dependent seizures. 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