{"id":"edd74ddc-e656-5ad8-9f4d-2edf7861cd40","stable_key":"52871722-4aa6-5453-a902-3e76356db327:resveratrol-sirt1-e230","predicate":"reduces_response","statement":"The E230K substitution attenuated resveratrol activation of human SIRT1 with an AMC substrate and a natural-amino-acid substrate without abolishing basal catalytic activity.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"26da91cf-987b-5492-91af-8bde8a4fd187","mechanism_event_label":"An enzyme residue contributes to selective activation.","subject":{"id":"f28bc345-4227-583b-ad1e-78dca173eeb7","slug":"human-sirt1-e230k","display_name":"Human SIRT1 E230K activation-defective variant","entity_type_key":"protein"},"object":{"id":"b8e1bfa9-c412-5f35-97af-cfc722123d27","slug":"sirt1","display_name":"SIRT1","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"26da91cf-987b-5492-91af-8bde8a4fd187","stable_key":"52871722-4aa6-5453-a902-3e76356db327:resveratrol-sirt1-e230-event","event_type":"observed_relationship","label":"An enzyme residue contributes to selective activation.","description":"The E230K substitution attenuated resveratrol activation of human SIRT1 with an AMC substrate and a natural-amino-acid substrate without abolishing basal catalytic activity.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"f28bc345-4227-583b-ad1e-78dca173eeb7","slug":"human-sirt1-e230k","display_name":"Human SIRT1 E230K activation-defective variant","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"b8e1bfa9-c412-5f35-97af-cfc722123d27","slug":"sirt1","display_name":"SIRT1","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"53549e32-e6b4-5f09-94e6-62867b015713","slug":"resveratrol","display_name":"Resveratrol","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_access","value_text":"Primary full text","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Recombinant mutagenesis; 40 micromolar resveratrol in the illustrated AMC assay.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Other figures use synthetic STACs; those interventions are not silently attributed to resveratrol.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Resveratrol collection; molecular form, preparation, species, exposure and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"resveratrol","display_name":"Resveratrol","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"An enzyme residue contributes to selective activation.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Evidence for a common mechanism of SIRT1 regulation by allosteric activators. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23471411/ · DOI 10.1126/science.1231097","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":"f31a792a-2abb-5f79-a926-6b1f5450ef23","evidence_kind":"source_excerpt","locator":"Lines 166-172","start_line":166,"end_line":172,"excerpt":"## resveratrol-sirt1-e230\nAn enzyme residue contributes to selective activation.\nThe E230K substitution attenuated resveratrol activation of human SIRT1 with an AMC substrate and a natural-amino-acid substrate without abolishing basal catalytic activity.\nModel: Recombinant mutagenesis; 40 micromolar resveratrol in the illustrated AMC assay.\nLimitations: Other figures use synthetic STACs; those interventions are not silently attributed to resveratrol.\nEvidence access: Primary full text\nEvidence for a common mechanism of SIRT1 regulation by allosteric activators. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23471411/ · DOI 10.1126/science.1231097","model_system":"Recombinant mutagenesis; 40 micromolar resveratrol in the illustrated AMC assay.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"Original curation paraphrase; evidence access and experimental limitations specified.","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"2844eda9-a122-5357-ae47-cd58227c5994","stable_key":"import-52871722-4aa6-5453-a902-3e76356db327","title":"Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19)","document_type":"imported_text","citation_label":"AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text.","file_path":"","sha256":"04885b4bee72f912a7f3f618f1b2bf79c944dbcb20500398c2729fc8228dcd9a","revision_id":"99504ff2-f1d3-5f4c-bc31-e1030d27a918","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"5201c9d2-00e8-5fbc-801c-b6ddf481494c","title":"Resveratrol and direct SIRT1 activation: the substrate-dependent dispute","kind":"contradiction","status":"open","why":"The 2010 paper concluded that resveratrol is not a direct SIRT1 activator after native-substrate failures. The 2013 studies support activation for selected native sequences and an activation-sensitive enzyme residue. The disputed general conclusion goes beyond merely different numerical results.","resolution":"Preserve both experiments and qualify the generalization: direct modulation can be substrate-selective, with stimulation, inhibition or no effect. This reconciles part of the assay dispute; it does not establish universal activation or the dominant target at human exposure. Draft corrections are not being recorded as conflicts.","created_at":"2026-09-19 08:33:56","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/5201c9d2-00e8-5fbc-801c-b6ddf481494c","sides":[{"conflict_id":"5201c9d2-00e8-5fbc-801c-b6ddf481494c","ordinal":0,"label":"Native-substrate failures and assay dependence","revision_id":"99504ff2-f1d3-5f4c-bc31-e1030d27a918","start_line":150,"end_line":156,"quote":"## resveratrol-sirt1-native-null\nSome original activation assays depended on the artificial reporter.\nResveratrol did not activate human SIRT1 on the tested unlabelled p53 peptide or full-length p53 and acetyl-CoA-synthetase substrates, while fluorophore-tagged peptide assays showed activation.\nModel: Biochemical comparison of labelled and native substrates.\nLimitations: This is a negative result for tested substrates, not proof that no native sequence can respond.\nEvidence access: Primary abstract\nSRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20061378/ · DOI 10.1074/jbc.M109.088682","source_key":"import-52871722-4aa6-5453-a902-3e76356db327","source_title":"Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19)","claim_ids":["f80d2c90-3070-5aaa-8006-aa518d5c3ac8"]},{"conflict_id":"5201c9d2-00e8-5fbc-801c-b6ddf481494c","ordinal":1,"label":"Physiological-sequence selectivity","revision_id":"99504ff2-f1d3-5f4c-bc31-e1030d27a918","start_line":158,"end_line":164,"quote":"## resveratrol-sirt1-sequence-selectivity\nSIRT1 is not a universal on/off switch for resveratrol.\nIn a 6,802-site physiological acetyl-peptide screen, resveratrol stimulated SIRT1 deacetylation of a small subset, inhibited another subset and left most sites largely unchanged; solution assays confirmed selected categories.\nModel: Peptide arrays and solution enzyme assays.\nLimitations: Peptides do not reproduce complete chromatin or whole-cell substrate competition.\nEvidence access: Primary full text\nSirt1 activation by resveratrol is substrate sequence-selective. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23524286/ · DOI 10.18632/aging.100542","source_key":"import-52871722-4aa6-5453-a902-3e76356db327","source_title":"Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19)","claim_ids":["1403c0c3-e2eb-5ec8-803a-43b45ae4dd97"]},{"conflict_id":"5201c9d2-00e8-5fbc-801c-b6ddf481494c","ordinal":2,"label":"Activation-sensitive SIRT1 residue","revision_id":"99504ff2-f1d3-5f4c-bc31-e1030d27a918","start_line":166,"end_line":172,"quote":"## resveratrol-sirt1-e230\nAn enzyme residue contributes to selective activation.\nThe E230K substitution attenuated resveratrol activation of human SIRT1 with an AMC substrate and a natural-amino-acid substrate without abolishing basal catalytic activity.\nModel: Recombinant mutagenesis; 40 micromolar resveratrol in the illustrated AMC assay.\nLimitations: Other figures use synthetic STACs; those interventions are not silently attributed to resveratrol.\nEvidence access: Primary full text\nEvidence for a common mechanism of SIRT1 regulation by allosteric activators. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23471411/ · DOI 10.1126/science.1231097","source_key":"import-52871722-4aa6-5453-a902-3e76356db327","source_title":"Resveratrol: metabolites, target selectivity and cross-nutrient mechanisms (2026-09-19)","claim_ids":["edd74ddc-e656-5ad8-9f4d-2edf7861cd40"]}]}],"corrections":[],"research":null}