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Reactivation of NADH Dehydrogenase (Complex I) Inhibited by 1‐Methyl‐4‐(4′‐Alkylphenyl)pyridinium Analogues: A Clue to the Nature of the Inhibition Site
Author(s) -
Krueger Matthew J.,
Sablin Sergey O.,
Ramsay Rona,
Singer Thomas P.
Publication year - 1993
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1993.tb13653.x
Subject(s) - submitochondrial particle , chemistry , binding site , rotenone , electron transport chain , stereochemistry , electron transport complex i , nadh dehydrogenase , biophysics , pyridinium , mitochondrion , dehydrogenase , biochemistry , enzyme , medicinal chemistry , respiratory chain , biology , protein subunit , gene
Expression of the neurotoxicity of 1‐methyl‐4‐phenyl‐1.2,3,6‐tetrahydropyridine, following oxidation to l‐methyl‐4‐phenylpyridinium ion (MPP + ), is believed to involve inhibition of mitochondrial electron transport from NADH dehydrogenase (complex l) to ubquinone. MPP + and its analogues have been shown to Mock electron transport at or near the same site as two powerful inhibitors of mitochondrial respiration, rotenone and piericidin A. All three types of inhibitors combine at two sites on NADH dehydrogenase, a hydrophilic and hydrophobic one, and occupancy of both sites is required for complete inhibition. Tetraphenylboron anion (TPB − ) in catalytic amounts is known to increase the effectiveness of positively charged MPP + analogues in blodclng mitochondrial respiration. A part of this effect involves facitation of the entry of MPP + oongeners into the hydrophobic site by ion pairing, as has been demonstrated in studies with submitochondrial particles (electron transport particles). This communication documents the fact that TPB − , when present in molar excess over the MPP + analogues, reverses the inhibition. This seems to involve again strong ion pairing. removal of the inhibitory analogue from one to the two binding sites, and concentration of the inhibitor in the membrane, so that only the hydrophobic binding site remains occupied, resulting in lowering of the inhibiti to 30–40%.