{"id":"7cd5e2d5-4141-585b-bfc2-d08acd444083","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-copper-s6-independent","predicate":"reduces","statement":"Regulation of S6 phosphorylation was prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting that AMPK and S6 phosphorylation are regulated independently by biguanides.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"07893bf1-02ef-5f72-ba49-89bf0c597839","mechanism_event_label":"Two of the drug’s effects depend on the metal in different ways, so they are separate routes.","subject":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"object":{"id":"2d6e2571-8f49-5e1b-98a9-7b0f5d0ca545","slug":"s6-phosphorylation","display_name":"Ribosomal protein S6 phosphorylation","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"07893bf1-02ef-5f72-ba49-89bf0c597839","stable_key":"8b3cf083-ea9c-54f5-b42b-bf1fef5b2978:metformin-copper-s6-independent-event","event_type":"biochemical_relationship","label":"Two of the drug’s effects depend on the metal in different ways, so they are separate routes.","description":"Regulation of S6 phosphorylation was prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting that AMPK and S6 phosphorylation are regulated independently by biguanides.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"15c12257-a056-5cee-900a-15f19b9d4115","slug":"biguanide-copper-complex","display_name":"Biguanide-copper coordination complex","entity_type_key":"chemical_species"},"role":"proposed_species","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"2d6e2571-8f49-5e1b-98a9-7b0f5d0ca545","slug":"s6-phosphorylation","display_name":"Ribosomal protein S6 phosphorylation","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/metformin-research/22492524.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56\", \"start_char\": 0, \"end_char\": 1526, \"text_sha256\": \"a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Copper sequestration and biguanide analogues in cells, with mitochondrial measurements","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Metformin and analogues with and without copper sequestration","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A metal-dependence result using chemical sequestration and structural analogues. It does not establish that copper status in a person changes the drug’s effect.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.","comparator":null,"unit":null,"notes":"","entity":{"slug":"metformin","display_name":"Metformin","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Cultured cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Two of the drug’s effects depend on the metal in different ways, so they are separate routes.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[metformin-p22492524] Cellular responses to the metal-binding properties of metformin. (2012). https://pubmed.ncbi.nlm.nih.gov/22492524/ DOI: 10.2337/db11-0961","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Mitochondria and cytoplasm","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"96613e69-b2a7-52a1-b17b-43c2856e83fe","evidence_kind":"source_excerpt","locator":"Lines 1360-1371","start_line":1360,"end_line":1371,"excerpt":"### metformin-copper-s6-independent\nRegulation of S6 phosphorylation was prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting that AMPK and S6 phosphorylation are regulated independently by biguanides.\nCondition category: normal\nnutrient_topic: Metformin research collection; topical membership is not evidence of a direct clinical effect, and pharmacological exposure is not dietary intake.\nplain_language: Two of the drug’s effects depend on the metal in different ways, so they are separate routes.\norganism: Cultured cells\ntissue_or_cell_type: Mitochondria and cytoplasm\nexperimental_model: Copper sequestration and biguanide analogues in cells, with mitochondrial measurements\nlimitations: A metal-dependence result using chemical sequestration and structural analogues. It does not establish that copper status in a person changes the drug’s effect.\nexposure: Metformin and analogues with and without copper sequestration\nevidence_span: {\"source_cache\": \"artifacts/metformin-research/22492524.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56\", \"start_char\": 0, \"end_char\": 1526, \"text_sha256\": \"a0b1587d871d78b3bccefc5a47b277191faf6bc3b070dbe43295a0b21a633c56\"}\n[metformin-p22492524] Cellular responses to the metal-binding properties of metformin. (2012). https://pubmed.ncbi.nlm.nih.gov/22492524/ DOI: 10.2337/db11-0961","model_system":"Copper sequestration and biguanide analogues in cells, with mitochondrial measurements","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. 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