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Titolo:
Three classes of inhibitors share a common binding domain in mitochondrialcomplex I (NADH : ubiquinone oxidoreductase)
Autore:
Okun, JG; Lummen, P; Brandt, U;
Indirizzi:
Univ Frankfurt Klinikum, Inst Biochem 1, D-60590 Frankfurt, Germany Univ Frankfurt Klinikum Frankfurt Germany D-60590 590 Frankfurt, Germany Hoechst Schering AgrEvo GMBH, Biochem Res, D-65926 Frankfurt, Germany Hoechst Schering AgrEvo GMBH Frankfurt Germany D-65926 rankfurt, Germany
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 5, volume: 274, anno: 1999,
pagine: 2625 - 2630
SICI:
0021-9258(19990129)274:5<2625:TCOISA>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
BOVINE HEART-MITOCHONDRIA; PHOTOSYNTHETIC REACTION CENTER; H-3 DIHYDROROTENONE BINDING; PROTON-TRANSLOCATING NADH; ELECTRON-TRANSPORT CHAIN; RESPIRATORY-CHAIN; SUBMITOCHONDRIAL PARTICLES; ESCHERICHIA-COLI; COENZYME-Q; REDUCTASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
58
Recensione:
Indirizzi per estratti:
Indirizzo: Brandt, U UnivD-60590urt Klinikum, Inst Biochem 1, ZBC Theodor Stern Kai 7,Haus 25B, Univ Frankfurt Klinikum ZBC Theodor Stern Kai 7,Haus 25B Frankfurt Germany D-60590
Citazione:
J.G. Okun et al., "Three classes of inhibitors share a common binding domain in mitochondrialcomplex I (NADH : ubiquinone oxidoreductase)", J BIOL CHEM, 274(5), 1999, pp. 2625-2630

Abstract

We have developed two independent methods to measure equilibrium binding of inhibitors to membrane bound and partially purified NADH:ubiquinone oxidoreductase (complex I) to characterize the binding sites for the great variety of hydrophobic compounds acting on this large and complicated enzyme. Taking advantage of a partial quench of fluorescence upon binding of the fenazaquin-type inhibitor 2-decyl-4-quinazolinyl amine to complex I in bovine submitochondrial particles, we determined a K-d of 17 +/- 3 nM and one binding site per complex I. Equilibrium binding studies with [H-3]dihydrorotenone and the aminopyrimidine [H-3]AE F119209 (4(cis-4-[H-3]isopropyl cyclohexylamino)-5-chloro-6-ethyl pyrimidine) using partially purified complex I from Musca domestica exhibited little unspecific binding and allowed reliable determination of dissociation constants. Competition experiments consistently demonstrated that all tested hydrophobic inhibitors of complex I share a common binding domain with partially overlapping sites. Although the rotenone site overlaps with both the piericidin A and the capsaicin site, the latter two sites do not overlap. This is in contrast to the interpretation of enzyme kinetics that have previously been used to define three classes of complex I inhibitors. The existence of only one large inhibitor binding pocket in the hydrophobic part of complex Iis discussed in the light of possible mechanisms of proton translocation.

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Documento generato il 19/01/20 alle ore 14:24:38