Activation of NO donors in mitochondria: peroxidase metabolism of (2-hydroxyamino-vinyl)-triphenyl-phosphonium by cytochrome c releases NO and protects cells against apoptosis.
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.
Stoyanovsky
Detcho A
DA
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA. stoyanovskyd@upmc.edu
Vlasova
Irina I
II
Belikova
Natalia A
NA
Kapralov
Alexandr
A
Tyurin
Vladimir
V
Greenberger
Joel S
JS
Kagan
Valerian E
VE
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
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