{"id":"9c2614d6-fdde-577b-82d4-b036fabc2a0c","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-tyr167-and-negative-effect","predicate":"causes","statement":"Changing Saccharomyces cerevisiae beta-tubulin residue phenylalanine 167 to tyrosine produced at least 3 to 4 fold decreased sensitivity to carbendazim and nocodazole and the mutant was cold sensitive, implying a direct effect on benzimidazole binding rather than a nonspecific increase in microtubule stability, but surprisingly the mutant had 8 fold increased sensitivity to benomyl, which is structurally identical to carbendazim except at position 1, suggesting that residue 167 interacts with benzimidazoles in the vicinity of the 1 position.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"35248409-5bdc-5ff1-81f6-7c15f76db517","mechanism_event_label":"The same mutation that resists one compound makes the organism more vulnerable to its near twin.","subject":{"id":"18f3376a-d34d-5e6b-94e1-cc819edaefed","slug":"beta-tubulin-tyr167","display_name":"Beta-tubulin carrying tyrosine at position 167","entity_type_key":"protein_state"},"object":{"id":"de0d4926-764b-531e-8fb9-961449221d21","slug":"benzimidazole-resistance","display_name":"Resistance to benzimidazole anthelmintics","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"35248409-5bdc-5ff1-81f6-7c15f76db517","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-tyr167-and-negative-effect-event","event_type":"biochemical_relationship","label":"The same mutation that resists one compound makes the organism more vulnerable to its near twin.","description":"Changing Saccharomyces cerevisiae beta-tubulin residue phenylalanine 167 to tyrosine produced at least 3 to 4 fold decreased sensitivity to carbendazim and nocodazole and the mutant was cold sensitive, implying a direct effect on benzimidazole binding rather than a nonspecific increase in microtubule stability, but surprisingly the mutant had 8 fold increased sensitivity to benomyl, which is structurally identical to carbendazim except at position 1, suggesting that residue 167 interacts with benzimidazoles in the vicinity of the 1 position.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"d67b7610-905f-5e26-bdde-06d7fc12d8e8","slug":"carbendazim","display_name":"Carbendazim","entity_type_key":"chemical_species"},"role":"resisted_compound","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"9119ba51-2ce8-5b18-9fc0-4eaf294b3229","slug":"nocodazole","display_name":"Nocodazole","entity_type_key":"chemical_species"},"role":"resisted_compound","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"831caace-2d1f-5f66-ace1-655fea2127b9","slug":"benomyl","display_name":"Benomyl","entity_type_key":"chemical_species"},"role":"potentiated_compound","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"208f0ecb-60b3-5bcc-824a-c3e63a7af93d","slug":"fungal-beta-tubulin","display_name":"Fungal beta-tubulin","entity_type_key":"protein"},"role":"affected_protein","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"18f3376a-d34d-5e6b-94e1-cc819edaefed","slug":"beta-tubulin-tyr167","display_name":"Beta-tubulin carrying tyrosine at position 167","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"de0d4926-764b-531e-8fb9-961449221d21","slug":"benzimidazole-resistance","display_name":"Resistance to benzimidazole anthelmintics","entity_type_key":"cellular_process"},"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":"evidence_span","value_text":"{\"source_cache\": \"artifacts/mebendazole-research/8641470.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"35145959fc480be6039e088de374d7549dddc6f298511a41d2a760e7fdb8f455\", \"start_char\": 0, \"end_char\": 917, \"text_sha256\": \"35145959fc480be6039e088de374d7549dddc6f298511a41d2a760e7fdb8f455\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Site-directed mutagenesis and gene replacement of Saccharomyces cerevisiae beta-tubulin residue 167","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Phenylalanine 167 changed to tyrosine, then tested against carbendazim, nocodazole and benomyl","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A clean genetic test in a tractable organism, and the cold sensitivity argues the effect is on binding rather than on general microtubule stability. Yeast beta-tubulin is not nematode beta-tubulin.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.","comparator":null,"unit":null,"notes":"","entity":{"slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Yeast","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The same mutation that resists one compound makes the organism more vulnerable to its near twin.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mbz-p8641470] Site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin: interaction between residue 167 and benzimidazole compounds. (1996). https://pubmed.ncbi.nlm.nih.gov/8641470/ DOI: 10.1016/0014-5793(96)00334-1","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Beta-tubulin","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":"a87d59c2-d795-5626-a03d-7339d3992eba","evidence_kind":"source_excerpt","locator":"Lines 303-314","start_line":303,"end_line":314,"excerpt":"### mbz-tyr167-and-negative-effect\nChanging Saccharomyces cerevisiae beta-tubulin residue phenylalanine 167 to tyrosine produced at least 3 to 4 fold decreased sensitivity to carbendazim and nocodazole and the mutant was cold sensitive, implying a direct effect on benzimidazole binding rather than a nonspecific increase in microtubule stability, but surprisingly the mutant had 8 fold increased sensitivity to benomyl, which is structurally identical to carbendazim except at position 1, suggesting that residue 167 interacts with benzimidazoles in the vicinity of the 1 position.\nCondition category: machinery_impairment\nnutrient_topic: Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.\nplain_language: The same mutation that resists one compound makes the organism more vulnerable to its near twin.\norganism: Yeast\ntissue_or_cell_type: Beta-tubulin\nexperimental_model: Site-directed mutagenesis and gene replacement of Saccharomyces cerevisiae beta-tubulin residue 167\nlimitations: A clean genetic test in a tractable organism, and the cold sensitivity argues the effect is on binding rather than on general microtubule stability. Yeast beta-tubulin is not nematode beta-tubulin.\nexposure: Phenylalanine 167 changed to tyrosine, then tested against carbendazim, nocodazole and benomyl\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/8641470.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"35145959fc480be6039e088de374d7549dddc6f298511a41d2a760e7fdb8f455\", \"start_char\": 0, \"end_char\": 917, \"text_sha256\": \"35145959fc480be6039e088de374d7549dddc6f298511a41d2a760e7fdb8f455\"}\n[mbz-p8641470] Site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin: interaction between residue 167 and benzimidazole compounds. (1996). https://pubmed.ncbi.nlm.nih.gov/8641470/ DOI: 10.1016/0014-5793(96)00334-1","model_system":"Site-directed mutagenesis and gene replacement of Saccharomyces cerevisiae beta-tubulin residue 167","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [mbz-p8641470] Site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin: interaction between residue 167 and benzimidazole compounds. (1996). https://pubmed.ncbi.nlm.nih.gov/8641470/ DOI: 10.1016/0014-5793(96)00334-1","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"06104773-03d0-5e5c-b9da-eb484e7be657","stable_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","title":"Mebendazole: the tubulin it binds, why that is selective, the crystal form that decides whether any of it works, and the off-target that became an oncology programme (2026-09-22)","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":"58b652636677e5033fd1dd555744485fcef18f21a97dcf68723fe072b656f413","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}