title: An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei.
abstract: Ascofuranone, a prenylphenol antibiotic isolated from a phytopathogenic fungus, Ascochyta visiae, strongly inhibited both glucose-dependent cellular respiration and glycerol-3-phosphate-dependent mitochondrial O2 consumption of long slender bloodstream forms of Trypanosoma brucei brucei. This inhibition was suggested to be due to inhibition of the mitochondrial electron-transport system, composed of glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) and plant-like alternative oxidase. Ascofuranone noncompetitively inhibited the reduced coenzyme Q1-dependent O2 uptake of the mitochondria with respect to ubiquinol (Ki = 2.38 nM). Therefore, the susceptible site is deduced to be the ubiquinone redox machinery which links the two enzyme activities. Further, ascofuranone in combination with glycerol completely blocked energy production, and potently inhibited the in vitro growth of the parasite. Our findings suggest that ascofuranone might be a promising candidate for the chemotherapeutic agents of African trypanosomiasis.
authors.affiliation: Department of Biochemistry, Niigata College of Pharmacy, Japan. minagawa@niigata-pharm.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Minagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Yabu
authors.forename: K
authors.initials: K
authors.lastname: Kita
authors.forename: K
authors.initials: K
authors.lastname: Nagai
authors.forename: N
authors.initials: N
authors.lastname: Ohta
authors.forename: K
authors.initials: K
authors.lastname: Meguro
authors.forename: S
authors.initials: S
authors.lastname: Sakajo
authors.forename: A
authors.initials: A
authors.lastname: Yoshimoto
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000494:pharmacology; D005994:Glycerophosphates / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000097:blood / Q000188:drug therapy / Q000469:parasitology; D014451:Ubiquinone / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D005994:Glycerophosphates; D012717:Sesquiterpenes; D014344:Trypanocidal Agents; D014451:Ubiquinone; C029620:alpha-glycerophosphoric acid; C006640:ascofuranone; D005947:Glucose; D005990:Glycerol