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Titolo:
CHARACTERIZATION OF THE INHIBITORY MECHANISM OF 1-METHYL-4-PHENYLPYRIDINIUM AND 4-PHENYLPYRIDINE ANALOGS IN INNER MEMBRANE PREPARATIONS
Autore:
GLUCK MR; KRUEGER MJ; RAMSAY RR; SABLIN SO; SINGER TP; NICKLAS WJ;
Indirizzi:
DEPT VET AFFAIRS MED CTR,DIV MOLEC BIOL,4150 CLEMENT ST,MAILSTOP 151-S SAN FRANCISCO CA 94121 DEPT VET AFFAIRS MED CTR,DIV MOLEC BIOL,4150 CLEMENT ST,MAILSTOP 151-S SAN FRANCISCO CA 94121 UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,DEPT NEUROL PISCATAWAY NJ 08854 UNIV CALIF SAN FRANCISCO,DEPT BIOCHEM BIOPHYS SAN FRANCISCO CA 94143 UNIV CALIF SAN FRANCISCO,DIV TOXICOL SAN FRANCISCO CA 94143
Titolo Testata:
The Journal of biological chemistry
fascicolo: 5, volume: 269, anno: 1994,
pagine: 3167 - 3174
SICI:
0021-9258(1994)269:5<3167:COTIMO>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
DOPAMINERGIC NEUROTOXIN 1-METHYL-4-PHENYLPYRIDINIUM; MITOCHONDRIAL RESPIRATION; NADH DEHYDROGENASE; PARKINSONS-DISEASE; MONOAMINE-OXIDASE; ELECTRON-TRANSPORT; REACTION SITES; BINDING-SITE; ION MPP+; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
38
Recensione:
Indirizzi per estratti:
Citazione:
M.R. Gluck et al., "CHARACTERIZATION OF THE INHIBITORY MECHANISM OF 1-METHYL-4-PHENYLPYRIDINIUM AND 4-PHENYLPYRIDINE ANALOGS IN INNER MEMBRANE PREPARATIONS", The Journal of biological chemistry, 269(5), 1994, pp. 3167-3174

Abstract

We have investigated the mechanism of the inhibition of membrane-bound NADH dehydrogenase by 1-methyl-4-phenylpyridinium (MPP+) and a series of its 4'-alkyl-substituted analogs of increasing hydrophobicity, aswell as their neutral, desmethyl congeners. Comparison of hydrophobicity, as measured by partition coefficients, with the IC50 for the inhibition of NADH oxidase activity in mitochondrial inner membrane preparations shows a negative correlation, but the cationic inhibitors are more effective than the neutral analogs with similar hydrophobicity. The presence of 10 mum tetraphenylboron (TPB-) potentiates the inhibitory power of positively charged analogs up to 4'-pentyl-MPP', while the neutral inhibitors are unaffected by TPB-. Without TPB-, the more hydrophilic analogs give incomplete inhibition, but the inclusion of TPB- permits the attainment of complete inhibition, accompanied by the appearance of sigmoidal titration curves. These data support the hypothesis that MPP+ analogs, like rotenone, are bound at two sites on the enzyme and occupancy of both is required for complete inhibition. TPB-, byforming ion pairs with the cationic analogs, facilitates their equilibration to both sites in membrane preparations. When present in molar excess over the MPP+ analog, TPB- partially reverses the inhibition bydecreasing its concentration in the more hydrophilic binding site. The effect of temperature and of pH on the IC50 values for inhibition support the concept of dual binding sites, and the pH dependence of the inhibition reveals the participation of two ionized protein groups in the binding, one of which may be a thiol group.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 12/07/20 alle ore 06:36:47