title: Activation of NO donors in mitochondria: peroxidase metabolism of (2-hydroxyamino-vinyl)-triphenyl-phosphonium by cytochrome c releases NO and protects cells against apoptosis.
abstract: In mitochondrial apoptosis, the formation of cytochrome c-cardiolipin complex ([CL-cyt c]) with peroxidase properties is an early event in the cascade of reactions that leads to cell death. Herein, we report the synthesis of a new prodrug, (2-hydroxyamino-vinyl)-triphenyl-phosphonium (HVTP), which compartmentalizes exclusively into mitochondria, undergoes a [CL-cyt c]-catalyzed bioactivation to nitric oxide (NO), inhibits peroxidase activity, and protects cells from apoptosis.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. stoyanovskyd@upmc.edu
authors.forename: Detcho A
authors.initials: DA
authors.lastname: Stoyanovsky
authors.forename: Irina I
authors.initials: II
authors.lastname: Vlasova
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Belikova
authors.forename: Alexandr
authors.initials: A
authors.lastname: Kapralov
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tyurin
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D002451:Cell Compartmentation; D045304:Cytochromes c / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006898:Hydroxylamines / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010544:Peroxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism
chemical_list: C528230:(2-hydroxyaminovinyl)triphenylphosphonium; D006898:Hydroxylamines; D020030:Nitric Oxide Donors; D009943:Organophosphorus Compounds; D010718:Phosphatidylserines; D003609:Dactinomycin; D009569:Nitric Oxide; D045304:Cytochromes c; D010544:Peroxidases; D053148:Caspase 3; D053179:Caspase 7