antamanide, a derivative of amanita phalloides, is a novel inhibitor of the mitochondrial permeability transition poreantamanide,phalloides纯化及结构鉴定的一个衍生物,它是一种新型线粒体通透性转换孔的抑制剂.pdfVIP

Antamanide, a Derivative of Amanita phalloides, Is a Novel Inhibitor of the Mitochondrial Permeability Transition Pore 1 2 2 2 1 3,4 Luca Azzolin , Nicola Antolini , Andrea Calderan , Paolo Ruzza , Marco Sciacovelli , Oriano Marin , 2 1,4 1 Stefano Mammi , Paolo Bernardi , Andrea Rasola * 1 Department of Biomedical Sciences University of Padova and CNR Institute of Neuroscience, Padova, Italy, 2 Department of Chemical Sciences, University of Padova and CNR Institute of Biomolecular Chemistry, Padova, Italy, 3 Department of Biological Chemistry, University of Padova, Padova, Italy, 4 Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy Abstract Antamanide is a cyclic decapeptide derived from the fungus Amanita phalloides. Here we show that antamanide inhibits the mitochondrial permeability transition pore, a central effector of cell death induction, by targeting the pore regulator cyclophilin D. Indeed, (i) permeability transition pore inhibition by antamanide is not additive with the cyclophilin D-binding drug cyclosporin A, (ii) the inhibitory action of antamanide on the pore requires phosphate, as previously shown for cyclosporin A; (iii) antamanide is ineffective in mitochondria or cells derived from cyclophilin D null animals, and (iv) abolishes CyP-D peptidyl-prolyl cis-trans isomerase activity. Permeability transition pore inhibition by antamanide needs two critical residues in the peptide ring, Phe6 and Phe9, and is additive with ubiquinone 0, which acts on th