{"id":"3614da79-04ff-5ee1-bb6f-c32c37dc69c2","stable_key":"e0ea2d6a-7429-5e9f-b774-41e5e3288da3:e-sig-delta-te-hmgcr-ubiquitination","predicate":"stimulates","statement":"Delta-tocotrienol stimulated HMG-CoA reductase ubiquitination in isolated SV-589 fibroblast membrane fractions supplemented with ubiquitin-activating enzyme; gamma-tocotrienol showed the same activity. The reconstituted result supported action without further tocotrienol metabolism.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"9ebdfa85-1970-558c-a64f-bfea31d87fb7","mechanism_event_label":"These tocotrienols promoted attachment of degradation tags to the cholesterol-synthesis enzyme in isolated cell membranes.","subject":{"id":"56c5cd15-b521-587d-a063-1cfd03644b46","slug":"delta-tocotrienol","display_name":"Delta-tocotrienol","entity_type_key":"small_molecule"},"object":{"id":"755e004d-e7e7-5dbc-b658-18f40dfea0cf","slug":"hmgcr-ubiquitination","display_name":"HMG-CoA reductase ubiquitination","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"9ebdfa85-1970-558c-a64f-bfea31d87fb7","stable_key":"e0ea2d6a-7429-5e9f-b774-41e5e3288da3:e-sig-delta-te-hmgcr-ubiquitination-event","event_type":"biochemical_relationship","label":"These tocotrienols promoted attachment of degradation tags to the cholesterol-synthesis enzyme in isolated cell membranes.","description":"Delta-tocotrienol stimulated HMG-CoA reductase ubiquitination in isolated SV-589 fibroblast membrane fractions supplemented with ubiquitin-activating enzyme; gamma-tocotrienol showed the same activity. The reconstituted result supported action without further tocotrienol metabolism.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"27fc7c66-efe2-57b6-988b-560bb242182d","slug":"gamma-tocotrienol","display_name":"Gamma-tocotrienol","entity_type_key":"small_molecule"},"role":"also active compound","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"a8b5e5e1-b5b5-551d-8fd4-72f7b45de78a","slug":"hmgcr","display_name":"HMG-CoA reductase (HMGCR)","entity_type_key":"protein"},"role":"ubiquitination substrate","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"10f91f6e-93c6-5ac9-a2cc-29e2bd83fa16","slug":"insig1","display_name":"Insulin-induced gene 1 protein (INSIG1)","entity_type_key":"protein"},"role":"regulatory machinery implicated by parallel experiments","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"a051b0a5-ab34-5c27-99bf-d1635082355d","slug":"insig2","display_name":"Insulin-induced gene 2 protein (INSIG2)","entity_type_key":"protein"},"role":"regulatory machinery implicated by parallel experiments","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"56c5cd15-b521-587d-a063-1cfd03644b46","slug":"delta-tocotrienol","display_name":"Delta-tocotrienol","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"755e004d-e7e7-5dbc-b658-18f40dfea0cf","slug":"hmgcr-ubiquitination","display_name":"HMG-CoA reductase ubiquitination","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"cross_nutrient","value_text":"false","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Isolated membranes from sterol-depleted SV-589 human fibroblasts; FLAG-ubiquitin and purified E1 assay","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Figure 5B: purified E1 5 µg/mL, FLAG-ubiquitin 0.1 mg/mL, ubiquitin-aldehyde 0.01 mg/mL and ATP-regenerating system; tocotrienol concentration not fully retrieved.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The assay does not prove direct molecular binding of tocotrienol to HMGCR or INSIG. No human cholesterol outcome follows from this reconstituted experiment.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Vitamin E research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"vitamin-e","display_name":"Vitamin E","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Homo sapiens","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"These tocotrienols promoted attachment of degradation tags to the cholesterol-synthesis enzyme in isolated cell membranes.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Fibroblast-derived membrane fractions","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"08724888-ee6a-5c7d-b53c-1ad1cea3103c","evidence_kind":"source_excerpt","locator":"Lines 1128-1139","start_line":1128,"end_line":1139,"excerpt":"### e-sig-delta-te-hmgcr-ubiquitination\nDelta-tocotrienol stimulated HMG-CoA reductase ubiquitination in isolated SV-589 fibroblast membrane fractions supplemented with ubiquitin-activating enzyme; gamma-tocotrienol showed the same activity. The reconstituted result supported action without further tocotrienol metabolism.\nCondition category: normal\nnutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: These tocotrienols promoted attachment of degradation tags to the cholesterol-synthesis enzyme in isolated cell membranes.\norganism: Homo sapiens\ntissue_or_cell_type: Fibroblast-derived membrane fractions\nexperimental_model: Isolated membranes from sterol-depleted SV-589 human fibroblasts; FLAG-ubiquitin and purified E1 assay\nlimitations: The assay does not prove direct molecular binding of tocotrienol to HMGCR or INSIG. No human cholesterol outcome follows from this reconstituted experiment.\nexposure: Figure 5B: purified E1 5 µg/mL, FLAG-ubiquitin 0.1 mg/mL, ubiquitin-aldehyde 0.01 mg/mL and ATP-regenerating system; tocotrienol concentration not fully retrieved.\ncross_nutrient: false\n[song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200","model_system":"Isolated membranes from sterol-depleted SV-589 human fibroblasts; FLAG-ubiquitin and purified E1 assay","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [song2006] Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. (2006). https://pubmed.ncbi.nlm.nih.gov/16831864/ DOI: 10.1074/jbc.m605575200","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"3ac41dba-4727-5116-a556-ac3bbb0dc41c","stable_key":"import-e0ea2d6a-7429-5e9f-b774-41e5e3288da3","title":"Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"a90b6565e092c6a2da07f74cf758792c2cf63b40746260c8ff12bd64322c36f4","revision_id":"956793d1-23e4-5397-9291-25c1732a8e02","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}