{"id":"a5b3ec16-0ce5-5df7-983a-5534bc298a6c","stable_key":"911fb3c7-8cc3-5667-b677-5682fab67648:histidine-amdhd-loss-mtx","predicate":"supports","statement":"CRISPR depletion of AMDHD1 reduced methotrexate sensitivity in the tested human cancer cells.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"c031b3e3-3aca-59ab-831d-6434eaec058b","mechanism_event_label":"An upstream histidine-breakdown step also changed drug sensitivity.","subject":{"id":"287d67fb-8f69-5a2d-a8be-b13c3332c143","slug":"amdhd1","display_name":"Human imidazolonepropionase / AMDHD1","entity_type_key":"protein"},"object":{"id":"b2f65ffa-5021-5f40-b1ac-1f220ed68c58","slug":"human-cancer-methotrexate-sensitivity","display_name":"Methotrexate sensitivity in human hematopoietic cancer cells","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"c031b3e3-3aca-59ab-831d-6434eaec058b","stable_key":"911fb3c7-8cc3-5667-b677-5682fab67648:histidine-amdhd-loss-mtx-event","event_type":"observed_relationship","label":"An upstream histidine-breakdown step also changed drug sensitivity.","description":"CRISPR depletion of AMDHD1 reduced methotrexate sensitivity in the tested human cancer cells.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"287d67fb-8f69-5a2d-a8be-b13c3332c143","slug":"amdhd1","display_name":"Human imidazolonepropionase / AMDHD1","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"b2f65ffa-5021-5f40-b1ac-1f220ed68c58","slug":"human-cancer-methotrexate-sensitivity","display_name":"Methotrexate sensitivity in human hematopoietic cancer cells","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"44374451-3436-5136-a8ae-5dcc6d8c353b","slug":"histidine","display_name":"L-Histidine","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"1f13ebf9-42c9-516e-b462-0e1b3952c2a2","slug":"methotrexate","display_name":"Methotrexate","entity_type_key":"small_molecule"},"role":"context_participant","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":"evidence_access","value_text":"Primary full text","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Human hematopoietic cancer-cell CRISPR experiments.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"histidine","display_name":"L-Histidine","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"An upstream histidine-breakdown step also changed drug sensitivity.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Histidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7","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":"77c4a8a8-ee4b-54d6-b4cf-f9f85b903744","evidence_kind":"source_excerpt","locator":"Lines 170-176","start_line":170,"end_line":176,"excerpt":"## histidine-amdhd-loss-mtx\nAn upstream histidine-breakdown step also changed drug sensitivity.\nCRISPR depletion of AMDHD1 reduced methotrexate sensitivity in the tested human cancer cells.\nModel: Human hematopoietic cancer-cell CRISPR experiments.\nLimitations: Enzyme depletion is different from lowering dietary histidine. Correction record: A 2022 author correction is indexed (PMID 35017686). The publisher-accessible record identifies corrected Fig. 1f, Extended Data Fig. 11, Supplementary Fig. 3 and source data for Figs. 1/2, including an erroneous doxorubicin replicate. Complete correction narrative was not accessible; its full impact is not independently cleared. The original study remains flagged corrected, and no comprehensive safety claim is made. https://www.nature.com/articles/s41586-021-03487-2\nEvidence access: Primary full text\nHistidine catabolism is a major determinant of methotrexate sensitivity. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29995852/ · DOI 10.1038/s41586-018-0316-7","model_system":"Human hematopoietic cancer-cell CRISPR experiments.","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":"ce59e6c9-1213-523b-9d0b-400b7a81cd1c","stable_key":"import-911fb3c7-8cc3-5667-b677-5682fab67648","title":"L-Histidine: supply, catabolism, histamine, receptors 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":"cb672530ec8b4a4542d0f3957e80ca76bb0449e9f988845b0f7681f623c4ec9b","revision_id":"19a7f26c-d9a1-5411-a81d-025f3d98a452","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}