Kinetic characterization of mitochondrial complex I inhibitors using annonaceous acetogenins.
The NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain is by far the largest and most complicated of the proton-translocating enzymes involved in the oxidative phosphorylation. Many clues regarding the electron pathways from matrix NADH to membrane ubiquinone and the links of this process with the translocation of protons are highly controversial. Different types of inhibitors become valuable tools to dissect the electron and proton pathways of this complex enzyme. Therefore, further knowledge of the mode of action of complex I inhibitors is needed to understand the underlying mechanism of energy conservation. This study presents for the first time a detailed exploration of the inhibitory action of the Annonaceous acetogenins, the most powerful inhibitors of the mammalian enzyme, taking as the head-series rolliniastatin-1, rolliniastatin-2, and corossolin. Despite their close chemical resemblance, each of them inhibits the complex I with different kinetic features reflecting differential binding to the enzyme.
Tormo
J R
JR
Facultat de Farmàcia, Universitat de València. Avgda., Vicent Andrés Estellés s/n, Burjassot (València), E-46100, Spain.
González
M C
MC
Cortes
D
D
Estornell
E
E
D000818:Animals; D002417:Cattle; D005663:Furans / Q000494:pharmacology*; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000201:enzymology*; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010936:Plant Extracts; D012402:Rotenone / Q000494:pharmacology; D013367:Submitochondrial Particles / Q000201:enzymology; D014451:Ubiquinone / Q000378:metabolism
D005663:Furans; D007783:Lactones; D010936:Plant Extracts; C112079:isomurisolenin; D012402:Rotenone; D009243:NAD; C061022:bullatacin; D014451:Ubiquinone; D016660:NAD(P)H Dehydrogenase (Quinone)