{"id":"5cb16e60-c487-565c-a1aa-7b855019e114","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-inhibits-malate-dehydrogenase","predicate":"inhibits","statement":"Of four benzimidazole anthelmintics tested on purified cytoplasmic and mitochondrial malate dehydrogenase from Ascaris suum, Fasciola hepatica and Moniezia expansa, mebendazole exhibited the highest percentage inhibitions, and the authors conclude that cytoplasmic and mitochondrial malate dehydrogenase regulating glycogen synthesis are the sites of mebendazole inhibitory activity while the sites for the other anthelmintics remain unclear.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"b85ce332-51ca-5f09-9d62-47a96c36617e","mechanism_event_label":"A rival account: the drug jams an enzyme of the worm’s sugar metabolism, and mebendazole does it hardest.","subject":{"id":"f8582a13-fc2e-5127-a61f-5b0594e54069","slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"},"object":{"id":"46eff024-2bdd-5c55-8c05-07c4c332e59b","slug":"parasite-malate-dehydrogenase","display_name":"Cytoplasmic and mitochondrial malate dehydrogenase of helminths","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"b85ce332-51ca-5f09-9d62-47a96c36617e","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-inhibits-malate-dehydrogenase-event","event_type":"biochemical_relationship","label":"A rival account: the drug jams an enzyme of the worm’s sugar metabolism, and mebendazole does it hardest.","description":"Of four benzimidazole anthelmintics tested on purified cytoplasmic and mitochondrial malate dehydrogenase from Ascaris suum, Fasciola hepatica and Moniezia expansa, mebendazole exhibited the highest percentage inhibitions, and the authors conclude that cytoplasmic and mitochondrial malate dehydrogenase regulating glycogen synthesis are the sites of mebendazole inhibitory activity while the sites for the other anthelmintics remain unclear.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"8f4f7666-1563-51d7-ba32-d38f3cbc90e4","slug":"mdh1","display_name":"Human cytosolic malate dehydrogenase / MDH1","entity_type_key":"protein"},"role":"inhibited_enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"ae767111-6c03-5941-8f1a-9f1d7f9bee83","slug":"mdh2","display_name":"Human mitochondrial malate dehydrogenase / MDH2","entity_type_key":"protein"},"role":"inhibited_enzyme","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"452e5883-cf79-5e73-b1c5-63aa4ae53a27","slug":"albendazole","display_name":"Albendazole","entity_type_key":"drug"},"role":"weaker_comparator","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"c557d26e-4eee-5ce2-aef1-8cef5e87fe5e","slug":"thiabendazole","display_name":"Thiabendazole","entity_type_key":"drug"},"role":"weaker_comparator","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"a27d0e8e-c0e4-5d13-97e8-6d77a98ce546","slug":"parasite-carbohydrate-metabolism","display_name":"Carbohydrate and energy metabolism of the parasite","entity_type_key":"cellular_process"},"role":"affected_process","stoichiometry":null,"state_label":"","sequence_order":4,"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":5,"notes":""},{"entity":{"id":"46eff024-2bdd-5c55-8c05-07c4c332e59b","slug":"parasite-malate-dehydrogenase","display_name":"Cytoplasmic and mitochondrial malate dehydrogenase of helminths","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":6,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/mebendazole-research/3617430.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"addd86672cc2c829b72354c05387892908f94c49f81e1236e372432c68a622fe\", \"start_char\": 0, \"end_char\": 589, \"text_sha256\": \"addd86672cc2c829b72354c05387892908f94c49f81e1236e372432c68a622fe\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Inhibition assays on purified cytoplasmic and mitochondrial malate dehydrogenase from three helminths","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Albendazole, parbendazole, mebendazole and thiabendazole on purified enzyme extracts","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A competing target claim. Enzyme inhibition percentages in purified extracts do not establish that this happens at therapeutic concentrations in a living parasite.","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":"Helminth","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A rival account: the drug jams an enzyme of the worm’s sugar metabolism, and mebendazole does it hardest.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mbz-p3617430] Inhibition of malate dehydrogenase enzymes by benzimidazole anthelmintics. (1987). https://pubmed.ncbi.nlm.nih.gov/3617430/ DOI: 10.1016/0304-4017(87)90048-3","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Ascaris suum, Fasciola hepatica and Moniezia expansa","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"734de0e0-91f9-5230-8f92-cadb8589d2a6","evidence_kind":"source_excerpt","locator":"Lines 238-249","start_line":238,"end_line":249,"excerpt":"### mbz-inhibits-malate-dehydrogenase\nOf four benzimidazole anthelmintics tested on purified cytoplasmic and mitochondrial malate dehydrogenase from Ascaris suum, Fasciola hepatica and Moniezia expansa, mebendazole exhibited the highest percentage inhibitions, and the authors conclude that cytoplasmic and mitochondrial malate dehydrogenase regulating glycogen synthesis are the sites of mebendazole inhibitory activity while the sites for the other anthelmintics remain unclear.\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: A rival account: the drug jams an enzyme of the worm’s sugar metabolism, and mebendazole does it hardest.\norganism: Helminth\ntissue_or_cell_type: Ascaris suum, Fasciola hepatica and Moniezia expansa\nexperimental_model: Inhibition assays on purified cytoplasmic and mitochondrial malate dehydrogenase from three helminths\nlimitations: A competing target claim. Enzyme inhibition percentages in purified extracts do not establish that this happens at therapeutic concentrations in a living parasite.\nexposure: Albendazole, parbendazole, mebendazole and thiabendazole on purified enzyme extracts\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/3617430.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"addd86672cc2c829b72354c05387892908f94c49f81e1236e372432c68a622fe\", \"start_char\": 0, \"end_char\": 589, \"text_sha256\": \"addd86672cc2c829b72354c05387892908f94c49f81e1236e372432c68a622fe\"}\n[mbz-p3617430] Inhibition of malate dehydrogenase enzymes by benzimidazole anthelmintics. (1987). https://pubmed.ncbi.nlm.nih.gov/3617430/ DOI: 10.1016/0304-4017(87)90048-3","model_system":"Inhibition assays on purified cytoplasmic and mitochondrial malate dehydrogenase from three helminths","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [mbz-p3617430] Inhibition of malate dehydrogenase enzymes by benzimidazole anthelmintics. (1987). https://pubmed.ncbi.nlm.nih.gov/3617430/ DOI: 10.1016/0304-4017(87)90048-3","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":[{"id":"5c29c8ca-8237-5d26-a4e8-d8126172428c","title":"Is the target tubulin, or the enzymes of parasite carbohydrate metabolism?","kind":"contradiction","status":"open","why":"The tubulin account is supported by direct binding measurements in several nematode species, by electron microscopy showing fewer and shorter microtubules, by the correlation between tubulin inhibition and egg hatch inhibition across the chemical series, and by a 1975 ultrastructural study in which the first change seen in the parasite gut is secretory granules stranded in the Golgi, which is what a transport failure looks like. Against that, mebendazole was the most potent of four benzimidazoles against purified helminth malate dehydrogenase, and in live infected mice it inhibited Echinococcus cyst wall pyruvate kinase by 85 to 88% and phosphoenolpyruvate carboxykinase by 90 to 92%, more than albendazole did. Those authors name these enzymes as the important site of attack. The records are not directly comparable: the tubulin work measures binding constants and the metabolic work measures percentage inhibition at administered doses, and neither set establishes what concentration reaches the enzyme in a treated human. Both are recorded; the loss of glycogen in the 1975 study is consistent with either.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 05:04:17","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/5c29c8ca-8237-5d26-a4e8-d8126172428c","sides":[{"conflict_id":"5c29c8ca-8237-5d26-a4e8-d8126172428c","ordinal":0,"label":"The drug grips worm tubulin hundreds of times more tightly than ours, which is the usual explanation for why it is safe.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":95,"end_line":106,"quote":"### mbz-selectivity-250-fold\nThe inhibition constants of mebendazole and fenbendazole for Ascaris suum embryonic tubulin were 1.9 x 10-8 and 6.5 x 10-8 molar while those for bovine brain tubulin were 7.3 x 10-6 and 1.7 x 10-5 molar, values 250 to 400 times greater, so that differential binding affinities between nematode and mammalian tubulin may explain the selective toxicity.\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: The drug grips worm tubulin hundreds of times more tightly than ours, which is the usual explanation for why it is safe.\norganism: Nematode and cattle\ntissue_or_cell_type: Embryonic nematode tubulin and bovine brain tubulin\nexperimental_model: Inhibition of tritiated colchicine binding to cytosolic tubulin from 8-day Ascaris suum embryos and from bovine brain\nlimitations: The founding selectivity result. It measures embryonic tubulin; the study in this collection that measured intestinal tubulin found a far smaller difference.\nexposure: Mebendazole and fenbendazole compared on the two tubulins in the same assay\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/7388055.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"5613d7fb281b4fd39b17bfdbafaf0ea823fb63b928048a9dd112fb71bf4cd2b7\", \"start_char\": 0, \"end_char\": 1209, \"text_sha256\": \"5613d7fb281b4fd39b17bfdbafaf0ea823fb63b928048a9dd112fb71bf4cd2b7\"}\n[mbz-p7388055] Interaction of anthelmintic benzimidazoles with Ascaris suum embryonic tubulin. (1980). https://pubmed.ncbi.nlm.nih.gov/7388055/ DOI: 10.1016/0304-4165(80)90431-6","source_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","source_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)","claim_ids":["cd993756-73c3-5f3e-bef0-2333ec27f3a5"]},{"conflict_id":"5c29c8ca-8237-5d26-a4e8-d8126172428c","ordinal":1,"label":"A rival account: the drug jams an enzyme of the worm’s sugar metabolism, and mebendazole does it hardest.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":238,"end_line":249,"quote":"### mbz-inhibits-malate-dehydrogenase\nOf four benzimidazole anthelmintics tested on purified cytoplasmic and mitochondrial malate dehydrogenase from Ascaris suum, Fasciola hepatica and Moniezia expansa, mebendazole exhibited the highest percentage inhibitions, and the authors conclude that cytoplasmic and mitochondrial malate dehydrogenase regulating glycogen synthesis are the sites of mebendazole inhibitory activity while the sites for the other anthelmintics remain unclear.\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: A rival account: the drug jams an enzyme of the worm’s sugar metabolism, and mebendazole does it hardest.\norganism: Helminth\ntissue_or_cell_type: Ascaris suum, Fasciola hepatica and Moniezia expansa\nexperimental_model: Inhibition assays on purified cytoplasmic and mitochondrial malate dehydrogenase from three helminths\nlimitations: A competing target claim. Enzyme inhibition percentages in purified extracts do not establish that this happens at therapeutic concentrations in a living parasite.\nexposure: Albendazole, parbendazole, mebendazole and thiabendazole on purified enzyme extracts\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/3617430.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"addd86672cc2c829b72354c05387892908f94c49f81e1236e372432c68a622fe\", \"start_char\": 0, \"end_char\": 589, \"text_sha256\": \"addd86672cc2c829b72354c05387892908f94c49f81e1236e372432c68a622fe\"}\n[mbz-p3617430] Inhibition of malate dehydrogenase enzymes by benzimidazole anthelmintics. (1987). https://pubmed.ncbi.nlm.nih.gov/3617430/ DOI: 10.1016/0304-4017(87)90048-3","source_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","source_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)","claim_ids":["5cb16e60-c487-565c-a1aa-7b855019e114"]},{"conflict_id":"5c29c8ca-8237-5d26-a4e8-d8126172428c","ordinal":2,"label":"In a live infection mebendazole shut down two sugar-handling enzymes almost completely, and did so harder than albendazole.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":251,"end_line":262,"quote":"### mbz-inhibits-pk-and-pepck\nPyruvate kinase and phosphoenolpyruvate carboxykinase activities in the Echinococcus granulosus cyst wall were markedly inhibited by mebendazole and albendazole while fumarate hydratase activity showed no apparent change, with inhibition rates in the mebendazole group of 85 to 88% and 90 to 92% respectively against 55.3% and 71.6% in the albendazole group, suggesting that these two enzymes may be an important site attacked by effective anti-hydatid drugs.\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: In a live infection mebendazole shut down two sugar-handling enzymes almost completely, and did so harder than albendazole.\norganism: Cestode\ntissue_or_cell_type: Hydatid cyst wall\nexperimental_model: Enzyme activity assays on Echinococcus granulosus cyst wall from infected mice after 7 to 14 days of treatment\nlimitations: An in vivo enzyme measurement with a head-to-head dose comparison, though the doses are not equipotent and the cyst wall is one tissue.\nexposure: Mebendazole 25 to 50, albendazole 300 and praziquantel 500 milligrams per kilogram daily by gavage\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/8010090.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"581715173f3b7176eda8a357166f1647196f646769b75ee7ca9070342a9c312b\", \"start_char\": 0, \"end_char\": 933, \"text_sha256\": \"581715173f3b7176eda8a357166f1647196f646769b75ee7ca9070342a9c312b\"}\n[mbz-p8010090] Effects of mebendazole, albendazole, and praziquantel on fumarate hydratase, pyruvate kinase, and phosphoenolpyruvate carboxykinase of Echinococcus granulosus cyst wall harbored in mice. (1994). https://pubmed.ncbi.nlm.nih.gov/8010090/","source_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","source_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)","claim_ids":["0aa3c843-80f7-58ed-9eee-a22cb5f410bc"]}]}],"corrections":[],"research":null}