The ability of Zofenoprilat, an angiotensin-converting enzyme inhibitor carrying a thiol group, to intervene in protein S-thiolation processes was tested on bovine lens aldose reductase (ALR2). Zofenoprilat, more susceptible to oxidation than glutathione (GSH), forms with this physiological thiol a rather stable mixed disulfide (ZSSG). ZSSG, whose generation through the transthiolation reaction between GSH and Zofenoprilat homodisulfide was shown to be enhanced by a micro-class glutathione S-transferase, appears to be a specific donor of the Zofenoprilat moiety in the S-thiolation processes. This is indicated by the apparent stability of ZSSG to reduction by GSH and by the specificity of the transfer of the group on ALR2, used as a protein model. Indeed, the S-thiolation of ALR2 by ZSSG occurred exclusively through the insertion of the Zofenoprilat moiety of ZSSG on the enzyme. The modified ALR2 is shown to retain the same activity of the native enzyme, but displays a reduced sensitivity to inhibition. The S-thiolation of specific target enzymes is proposed as an event potentially relevant for the antioxidant action of Zofenoprilat.
Zofenoprilat-Glutathione mixed disulfide as a specific S-thiolating agent of bovine lens aldose reductase
DAL MONTE, MASSIMO;DEL CORSO, ANTONELLA;MOSCHINI, ROBERTA;CAPPIELLO, MARIO;MURA, UMBERTO
2005-01-01
Abstract
The ability of Zofenoprilat, an angiotensin-converting enzyme inhibitor carrying a thiol group, to intervene in protein S-thiolation processes was tested on bovine lens aldose reductase (ALR2). Zofenoprilat, more susceptible to oxidation than glutathione (GSH), forms with this physiological thiol a rather stable mixed disulfide (ZSSG). ZSSG, whose generation through the transthiolation reaction between GSH and Zofenoprilat homodisulfide was shown to be enhanced by a micro-class glutathione S-transferase, appears to be a specific donor of the Zofenoprilat moiety in the S-thiolation processes. This is indicated by the apparent stability of ZSSG to reduction by GSH and by the specificity of the transfer of the group on ALR2, used as a protein model. Indeed, the S-thiolation of ALR2 by ZSSG occurred exclusively through the insertion of the Zofenoprilat moiety of ZSSG on the enzyme. The modified ALR2 is shown to retain the same activity of the native enzyme, but displays a reduced sensitivity to inhibition. The S-thiolation of specific target enzymes is proposed as an event potentially relevant for the antioxidant action of Zofenoprilat.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
