Identifying and Characterizing Binding Sites on the Irreversible Inhibition of Human Glutathione S-Transferase P1-1 by S-Thiocarbamoylation
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Quesada Soriano, Indalecio; Primavera, Alessandra; Casas Solvas, Juan Manuel; Téllez Sanz, Ramiro José; Barón Bravo, Carmen Francisca; [et al.]Fecha
2012-06-27Resumen
Human glutathione S-transferase P1-1 (hGST P1-1) is involved in cell detoxification processes through the conjugation of its natural substrate, reduced glutathione (GSH), with xenobiotics. GSTs are known to be overexpressed in tumors, and naturally occurring isothiocyanates, such as benzyl isothiocyanate (BITC), are effective cancer chemopreventive compounds. To identify and characterize the potential inhibitory mechanisms of GST P1-1 induced by isothiocyanate conjugates, we studied the binding of GST P1-1 and some cysteine mutants to the BITC–SG conjugate as well as to the synthetic S-(N-benzylcarbamoylmethyl)glutathione conjugate (BC–SG). We report here the inactivation of GST P1-1 through the covalent modification of two Cys47 residues per dimer and one Cys101. The evidence has been compiled by isothermal titration calorimetry (ITC) and electrospray ionization mass spectrometry (ESI-MS). ITC experiments suggest that the BITC–SG conjugate generates adducts with Cys47 and Cys101 at ph...
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Calorimetry
Binding
Human Glutathione S-Transferase
benzyl isothiocyanate