Evidence that the inhibition sites of the neurotoxic amine 1-methyl-4-phenylpyridinium (MPP+) and of the respiratory chain inhibitor piericidin A are the same.
1-Methyl-4-phenylpyridinium (MPP+), the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), interrupts mitochondrial electron transfer at the NADH dehydrogenase-ubiquinone junction, as do the respiratory chain inhibitors rotenone, piericidin A and barbiturates. Proof that these classical respiratory chain inhibitors and MPP+ react at the same site in the complex NADH dehydrogenase molecule has been difficult to obtain because none of these compounds bind covalently to the target. The 4'-alkyl derivatives of MPP+ inhibit NADH oxidation in submitochondrial particles at much lower concentrations than does MPP+ itself, but still dissociate on washing the membrane preparations, with consequent re-activation of the enzyme. The MPP+ analogues with short alkyl chains prevent the binding of 14C-labelled piericidin A to the membrane and thus must act at the same site, but analogues with alkyl chains longer than heptyl do not prevent binding of [14C]piericidin.
Ramsay
R R
RR
Department of Biochemistry and Biophysics, University of California, San Francisco 94143.
Krueger
M J
MJ
Youngster
S K
SK
Singer
T P
TP
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002417:Cattle; D002498:Centrifugation; D004579:Electron Transport; D004789:Enzyme Activation; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology
D001463:Barbiturates; D002250:Carbon Radioisotopes; D009097:Multienzyme Complexes; D011725:Pyridines; D012402:Rotenone; C100213:piericidin A; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D009245:NADH Dehydrogenase; D015655:1-Methyl-4-phenylpyridinium