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Titolo:
KINETICS AND MECHANISM OF THE REACTION BETWEEN SERUM-ALBUMIN AND AURANOFIN (AND ITS ISOPROPYL ANALOG) IN-VITRO
Autore:
ROBERTS JR; XIAO J; SCHLEISMAN B; PARSONS DJ; SHAW CF;
Indirizzi:
UNIV WISCONSIN,DEPT CHEM MILWAUKEE WI 53201 UNIV WISCONSIN,DEPT CHEM MILWAUKEE WI 53201 SIMULAT DYNAM INC MILWAUKEE WI 53211
Titolo Testata:
Inorganic chemistry
fascicolo: 2, volume: 35, anno: 1996,
pagine: 424 - 433
SICI:
0020-1669(1996)35:2<424:KAMOTR>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
NUCLEAR MAGNETIC-RESONANCE; LIGAND-EXCHANGE REACTIONS; BLOOD-CELLS; GOLD; GLUTATHIONE; COMPETITION; BINDING; COMPLEX; EFFLUX; RATES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
42
Recensione:
Indirizzi per estratti:
Citazione:
J.R. Roberts et al., "KINETICS AND MECHANISM OF THE REACTION BETWEEN SERUM-ALBUMIN AND AURANOFIN (AND ITS ISOPROPYL ANALOG) IN-VITRO", Inorganic chemistry, 35(2), 1996, pp. 424-433

Abstract

The first detailed kinetic analysis and mechanistic interpretation ofthe reactions between serum albumin and the second-generation gold drug Auranofin [Et(3)PAuSATg = ,3,4,6-tetra-O-acetyl-1-beta-D-glucopyranosato-S-) gold(I)] and its triisopropylphosphine analogue, iPr(3)PAuSATg, in vitro are reported. The reactions were investigated using Penefsky spun columns and NMR saturation transfer methods. Under the Penefsky chromatography conditions with 0.4-0.6 mM albumin and a wide range of Et(3)PAuSATg concentrations, the reaction is biphasic. The fast phase is apparently first order in albumin with a rate constant [k(1) = 3.4 +/- 0.3 x 10(-2) s(-1)] that decreases slightly in magnitude and becomes intermediate in order at low gold concentrations, [Et(3)PAuSATg][AlbSHH]; it accounts for similar to 95% of the Au(I) that binds. A minor, slower step [k(2) = 2.3 +/- 0.3 x 10(-3) s(-1)], which accounts for only 5% of the reaction, is also first order with respect to albumin, and zero order with respect to auranofin. For iPr(3)PAuSATg, only the first step was observed, k(1) = (1.4 +/- 0.1) x 10(-2) s(-1), and is first order in albumin and independent of the iPr(3)PAuSATg concentration. P-31-NMR saturation transfer experiments utilizing iPr(3)PAuSATg, under equilibrium conditions, yielded second-order rate constants for both the forward (1.2 x 10(2) M(-1) s(-1)) and the reverse (3.9 x 10(1) M(-1) s(-1)) directions. A multistep mechanism involving a conformationally altered albumin species was developed. Albumin domain IA opens with concomitant Cys-34 rearrangement, allowing facile gold binding and exchange, and then closes. In conjunction with the steady-stateapproximation, this mechanism accounts for the different reaction orders observed under the two set of conditions. The rate-determining conformational change of albumin governs the reaction as monitored by thePenefsky columns. Rapid second order exchange of R(3)PAuSATg at the exposed Cys-34 residue is observed under the NMR conditions. The mechanism predicts that under physiological conditions where [Et(3)PAuSATg] is 10-25 mu M, the reaction will be second order and rapid with a rateconstant of 8 +/- 2 x 10(2) M(-1) s(-1). The Penefsky spun columns revealed a previously unreported and novel binding mechanism, association of auranofin in the pocket of albumin-disulfide species, which was confirmed by Hummel-Dreyer gel chromatographic techniques under equilibrium conditions. This albumin-auranofin complex (AlbSSR-Et(3)PAuSATg) is weakly hound and readily dissociates during conventional gel exclusion chromatography.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/10/20 alle ore 08:36:09