{"id":"62875c04-3464-598a-82ad-5b4f1ffb8ac2","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-slow-release-is-the-point","predicate":"binds","statement":"Association of tritiated mebendazole to Haemonchus contortus tubulin was rapid at 2.6 x 10(5) per molar per minute but dissociation was slow at 1.58 x 10(-3) per minute, giving a kinetic affinity constant of 1.6 x 10(8) per molar against an equilibrium estimate of 5.3 x 10(6) per molar, and the slow dissociation from nematode tubulin, which contrasts with rapid dissociation from mammalian tubulin, supports the view that selective toxicity results from a difference between the affinities of mammalian and nematode tubulins.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"981608a9-1a53-57e1-9aab-de5af2d8783f","mechanism_event_label":"It binds worm tubulin quickly and then stays there; on ours it falls straight off again.","subject":{"id":"f8582a13-fc2e-5127-a61f-5b0594e54069","slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"},"object":{"id":"bd64884e-6ee7-55df-9993-c2887f5a50df","slug":"nematode-beta-tubulin","display_name":"Nematode beta-tubulin","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"981608a9-1a53-57e1-9aab-de5af2d8783f","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-slow-release-is-the-point-event","event_type":"biochemical_relationship","label":"It binds worm tubulin quickly and then stays there; on ours it falls straight off again.","description":"Association of tritiated mebendazole to Haemonchus contortus tubulin was rapid at 2.6 x 10(5) per molar per minute but dissociation was slow at 1.58 x 10(-3) per minute, giving a kinetic affinity constant of 1.6 x 10(8) per molar against an equilibrium estimate of 5.3 x 10(6) per molar, and the slow dissociation from nematode tubulin, which contrasts with rapid dissociation from mammalian tubulin, supports the view that selective toxicity results from a difference between the affinities of mammalian and nematode tubulins.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"3394b04b-6dc0-528b-8e94-0644d5d33f45","slug":"mammalian-brain-tubulin","display_name":"Mammalian brain tubulin","entity_type_key":"protein"},"role":"contrasting_protein","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"09b9bd29-555c-5fa9-8327-9916a82cc0a8","slug":"benzimidazole-tubulin-complex","display_name":"The benzimidazole-tubulin complex","entity_type_key":"protein_complex"},"role":"formed_complex","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"f8582a13-fc2e-5127-a61f-5b0594e54069","slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"bd64884e-6ee7-55df-9993-c2887f5a50df","slug":"nematode-beta-tubulin","display_name":"Nematode beta-tubulin","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/mebendazole-research/1459788.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"b34533a3360a1b113dca959ed53c0c5cf9f7efe61403c2b498146c90e7085bb1\", \"start_char\": 0, \"end_char\": 1160, \"text_sha256\": \"b34533a3360a1b113dca959ed53c0c5cf9f7efe61403c2b498146c90e7085bb1\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Kinetic and equilibrium binding of tritiated mebendazole to tubulin from third-stage Haemonchus contortus larvae","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Association and dissociation rate constants measured in partially purified preparations and crude cytosol","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Separates the rate of binding from the rate of release, which an equilibrium measurement cannot. The kinetic and equilibrium constants differ about thirtyfold and the authors argue for the kinetic value.","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":"Nematode","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"It binds worm tubulin quickly and then stays there; on ours it falls straight off again.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mbz-p1459788] The kinetics of mebendazole binding to Haemonchus contortus tubulin. (1992). https://pubmed.ncbi.nlm.nih.gov/1459788/ DOI: 10.1016/0020-7519(92)90051-l","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Larval nematode tubulin","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"877f42bb-dd43-5785-9597-8a2432721145","evidence_kind":"source_excerpt","locator":"Lines 147-158","start_line":147,"end_line":158,"excerpt":"### mbz-slow-release-is-the-point\nAssociation of tritiated mebendazole to Haemonchus contortus tubulin was rapid at 2.6 x 10(5) per molar per minute but dissociation was slow at 1.58 x 10(-3) per minute, giving a kinetic affinity constant of 1.6 x 10(8) per molar against an equilibrium estimate of 5.3 x 10(6) per molar, and the slow dissociation from nematode tubulin, which contrasts with rapid dissociation from mammalian tubulin, supports the view that selective toxicity results from a difference between the affinities of mammalian and nematode tubulins.\nCondition category: normal\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: It binds worm tubulin quickly and then stays there; on ours it falls straight off again.\norganism: Nematode\ntissue_or_cell_type: Larval nematode tubulin\nexperimental_model: Kinetic and equilibrium binding of tritiated mebendazole to tubulin from third-stage Haemonchus contortus larvae\nlimitations: Separates the rate of binding from the rate of release, which an equilibrium measurement cannot. The kinetic and equilibrium constants differ about thirtyfold and the authors argue for the kinetic value.\nexposure: Association and dissociation rate constants measured in partially purified preparations and crude cytosol\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/1459788.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"b34533a3360a1b113dca959ed53c0c5cf9f7efe61403c2b498146c90e7085bb1\", \"start_char\": 0, \"end_char\": 1160, \"text_sha256\": \"b34533a3360a1b113dca959ed53c0c5cf9f7efe61403c2b498146c90e7085bb1\"}\n[mbz-p1459788] The kinetics of mebendazole binding to Haemonchus contortus tubulin. 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