Two binding sites of inhibitors in NADH: ubiquinone oxidoreductase (complex I). Relationship of one site with the ubiquinone-binding site of bacterial glucose:ubiquinone oxidoreductase.
The effect of ten naturally occurring and two synthetic inhibitors of NADH:ubiquinone oxidoreductase (complex I) of bovine heart, Neurospora crassa and Escherichia coli and glucose:ubiquinone oxidoreductase (glucose dehydrogenase) of Gluconobacter oxidans was investigated. These inhibitors could be divided into two classes with regard to their specificity and mode of action. Class I inhibitors, including the naturally occurring piericidin A, annonin VI, phenalamid A2, aurachins A and B, thiangazole and the synthetic fenpyroximate, inhibit complex I from all three species in a partially competitive manner and glucose dehydrogenase in a competitive manner, both with regard to ubiquinone. Class II inhibitors including the naturally occurring rotenone, phenoxan, aureothin and the synthetic benzimidazole inhibit complex I from all species in an non-competitive manner, but have no effect on the glucose dehydrogenase. Myxalamid PI could not be classified as above because it inhibits only the mitochondrial complex I and in a competitive manner. All inhibitors affect the electron-transfer step from the high-potential iron-sulphur cluster to ubiquinone. Class I inhibitors appear to act directly at the ubiquinone-catalytic site which is related in complex I and glucose dehydrogenase.
Friedrich
T
T
Institut für Biochemie, Heinrich-Heine-Universität Düsseldorf, Germany.
van Heek
P
P
Leif
H
H
Ohnishi
T
T
Forche
E
E
Kunze
B
B
Jansen
R
R
Trowitzsch-Kienast
W
W
Höfle
G
G
Reichenbach
H
H
D016947:Acetobacteraceae / Q000201:enzymology*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology*; D042843:Glucose 1-Dehydrogenase; D005948:Glucose Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007425:Intracellular Membranes / Q000201:enzymology; D007700:Kinetics; D008929:Mitochondria, Heart / Q000201:enzymology*; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009492:Neurospora crassa / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014451:Ubiquinone / Q000378:metabolism*
D004791:Enzyme Inhibitors; D014451:Ubiquinone; D005948:Glucose Dehydrogenases; D042843:Glucose 1-Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone)