{"id":"4c01fb7f-ee4c-53cc-9983-2a536c32f62d","stable_key":"6d38d43e-01e4-5641-93be-65654271e242:zinc-enz-znt-mutant-no-activity","predicate":"fails_to_restore_activity_of","statement":"Reconstitution of ZnT5-ZnT6 with transport-incompetent ZnT5 did not restore TNAP activity.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"08e03a59-b266-56cc-becc-409c36482a25","mechanism_event_label":"Protecting the enzyme protein is insufficient when the complex cannot deliver zinc.","subject":{"id":"c47331fb-eb77-5252-90f6-8770495ec516","slug":"slc30a5-transport-incompetent-2011","display_name":"Transport-incompetent human ZnT5 study state","entity_type_key":"protein_state"},"object":{"id":"3148c377-9b4c-56ca-bc36-081bf1905d57","slug":"alpl","display_name":"Tissue-nonspecific alkaline phosphatase ALPL / TNAP","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"08e03a59-b266-56cc-becc-409c36482a25","stable_key":"6d38d43e-01e4-5641-93be-65654271e242:zinc-enz-znt-mutant-no-activity-event","event_type":"biochemical_relationship","label":"Protecting the enzyme protein is insufficient when the complex cannot deliver zinc.","description":"Reconstitution of ZnT5-ZnT6 with transport-incompetent ZnT5 did not restore TNAP activity.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"a483be20-7a24-5fca-8016-0b0e2032fdba","slug":"slc30a5","display_name":"Human zinc transporter 5 / ZnT5","entity_type_key":"protein"},"role":"transporter_component","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"0bb32d07-f10b-55f5-b4ae-157f25baceca","slug":"slc30a6","display_name":"Human zinc transporter 6 / ZnT6","entity_type_key":"protein"},"role":"transporter_component","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"39936fe1-d2f5-5328-ae8b-fa92e57da591","slug":"slc30a7","display_name":"Human zinc transporter 7 / ZnT7","entity_type_key":"protein"},"role":"parallel_transporter","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"49c806c2-7041-5020-8b3b-fa04ffa122ac","slug":"zinc-ion","display_name":"Zinc(II) ion","entity_type_key":"ion"},"role":"delivered_cofactor","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"c47331fb-eb77-5252-90f6-8770495ec516","slug":"slc30a5-transport-incompetent-2011","display_name":"Transport-incompetent human ZnT5 study state","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"3148c377-9b4c-56ca-bc36-081bf1905d57","slug":"alpl","display_name":"Tissue-nonspecific alkaline phosphatase ALPL / TNAP","entity_type_key":"protein"},"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":"cross_nutrient","value_text":"false","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Transport-incompetent ZnT5 variant with ZnT6, compared with functional loading machinery.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Zinc research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"zinc","display_name":"Zinc","entity_type_key":"nutrient_element"}},{"dimension":"organism","value_text":"Gallus gallus cell model with human proteins","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Protecting the enzyme protein is insufficient when the complex cannot deliver zinc.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Chicken DT40 early secretory pathway","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":"47f9315a-3ca9-5349-8930-54e99eff4441","evidence_kind":"source_excerpt","locator":"Lines 807-818","start_line":807,"end_line":818,"excerpt":"### zinc-enz-znt-mutant-no-activity\nReconstitution of ZnT5-ZnT6 with transport-incompetent ZnT5 did not restore TNAP activity.\nCondition category: machinery_impairment\nnutrient_topic: Zinc research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Protecting the enzyme protein is insufficient when the complex cannot deliver zinc.\norganism: Gallus gallus cell model with human proteins\ntissue_or_cell_type: Chicken DT40 early secretory pathway\nexperimental_model: Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation\nlimitations: Primary abstract-level evidence in engineered chicken DT40 cells with transporter complementation. Not a human dietary deficiency or supplementation trial; assay exposure amounts and mutant-specific residue effects are not inferred.\nexposure: Transport-incompetent ZnT5 variant with ZnT6, compared with functional loading machinery.\ncross_nutrient: false\n[zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. (2011). https://pubmed.ncbi.nlm.nih.gov/21402707/ DOI: 10.1074/jbc.m111.227173","model_system":"Engineered chicken DT40 cells with ZnT gene disruption and transporter re-expression; TNAP activation","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [zinc-enz-znt-tnap2011] Tissue nonspecific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway. 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