{"id":"a1971155-807e-53ef-9165-7b8b4e0bafd5","stable_key":"1deb434a-3547-51a0-a038-87b1ce79ec38:vd-act-cyp2r1-l99p","predicate":"impairs_production","statement":"The patient-derived human CYP2R1 Leu99Pro variant lost detectable D3 25-hydroxylase activity in the expression assays.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"cafa286f-7847-5264-8003-fd7afc1ac9a7","mechanism_event_label":"A CYP2R1 mutation can break the first D3 activation step.","subject":{"id":"6fd3b4a6-2941-574c-8182-5d2790812ccf","slug":"cyp2r1-l99p","display_name":"Human CYP2R1 L99P variant","entity_type_key":"protein_state"},"object":{"id":"6bd73bd2-1f0a-5caa-ba69-7ce1b75364bb","slug":"calcifediol","display_name":"Calcifediol / 25-hydroxyvitamin D3","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"cafa286f-7847-5264-8003-fd7afc1ac9a7","stable_key":"1deb434a-3547-51a0-a038-87b1ce79ec38:vd-act-cyp2r1-l99p-event","event_type":"biochemical_relationship","label":"A CYP2R1 mutation can break the first D3 activation step.","description":"The patient-derived human CYP2R1 Leu99Pro variant lost detectable D3 25-hydroxylase activity in the expression assays.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"54fd3aae-6183-5f9a-827e-f4dd7683eea7","slug":"cyp2r1","display_name":"Human vitamin D 25-hydroxylase / CYP2R1","entity_type_key":"protein"},"role":"normal_enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"6fd3b4a6-2941-574c-8182-5d2790812ccf","slug":"cyp2r1-l99p","display_name":"Human CYP2R1 L99P variant","entity_type_key":"protein_state"},"role":"impaired_enzyme","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"b162e431-b442-5400-9335-ec91f7875a4e","slug":"cholecalciferol","display_name":"Cholecalciferol","entity_type_key":"small_molecule"},"role":"substrate","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"6bd73bd2-1f0a-5caa-ba69-7ce1b75364bb","slug":"calcifediol","display_name":"Calcifediol / 25-hydroxyvitamin D3","entity_type_key":"small_molecule"},"role":"product","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"cross_nutrient","value_text":"false","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"evidence_location","value_text":"Results, Figures 3-5 and primary abstract.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Patient-derived allele expressed in cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"L99P versus wild-type CYP2R1; D3 biochemical/reporting assays.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The patient had residual circulating metabolites and responded to D2 treatment; this does not prove zero whole-body activation or zero residual D2 activity.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient","value_text":"Vitamin D2 and D3","comparator":null,"unit":null,"notes":"","entity":{"slug":"vitamin-d","display_name":"Vitamin D2 and D3","entity_type_key":"chemical_species"}},{"dimension":"nutrient_topic","value_text":"Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"vitamin-d","display_name":"Vitamin D2 and D3","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Homo sapiens protein","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A CYP2R1 mutation can break the first D3 activation step.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[cheng2004] Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. (2004). https://pubmed.ncbi.nlm.nih.gov/15128933/ DOI: 10.1073/pnas.0402490101","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"heterologous expression model","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":"1adb6a71-0f9d-5954-a416-cad428ccc46a","evidence_kind":"source_excerpt","locator":"Lines 362-375","start_line":362,"end_line":375,"excerpt":"### vd-act-cyp2r1-l99p\nThe patient-derived human CYP2R1 Leu99Pro variant lost detectable D3 25-hydroxylase activity in the expression assays.\nCondition category: machinery_impairment\nnutrient_topic: Vitamin D2 and D3 research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: A CYP2R1 mutation can break the first D3 activation step.\norganism: Homo sapiens protein\ntissue_or_cell_type: heterologous expression model\nexperimental_model: Patient-derived allele expressed in cells\nlimitations: The patient had residual circulating metabolites and responded to D2 treatment; this does not prove zero whole-body activation or zero residual D2 activity.\nexposure: L99P versus wild-type CYP2R1; D3 biochemical/reporting assays.\ncross_nutrient: false\nevidence_location: Results, Figures 3-5 and primary abstract.\nnutrient: Vitamin D2 and D3\n[cheng2004] Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. 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