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Originally published In Press as doi:10.1074/jbc.M102344200 on August 31, 2001

J. Biol. Chem., Vol. 276, Issue 45, 42138-42145, November 9, 2001
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Human Glutathione Transferase P1-1 and Nitric Oxide Carriers
A NEW ROLE FOR AN OLD ENZYME*

Mario Lo Belloab, Marzia Nuccetellia, Anna M. Caccuria, Lorenzo Stellacl, Michael W. Parkerde, Jamie Rossjohndf, William J. McKinstrydg, Alessia F. Mozzih, Giorgio Federicii, Francesca Polizioa, Jens Z. Pedersenaj, and Giorgio Ricciak

From the Departments of a Biology, c Chemistry, and h Internal Medicine, University of Rome "Tor Vergata," 00133 Rome, Italy, the d Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia, and the i Children's Hospital l Istituto di Ricerca e Cura a Carattere Scientifico "Bambino Gesù" 00165, Rome, Italy

S-Nitrosoglutathione and the dinitrosyl-diglutathionyl iron complex are involved in the storage and transport of NO in biological systems. Their interactions with the human glutathione transferase P1-1 may reveal an additional physiological role for this enzyme. In the absence of GSH, S-nitrosoglutathione causes rapid and stable S-nitrosylation of both the Cys47 and Cys101 residues. Ion spray ionization-mass spectrometry ruled out the possibility of S-glutathionylation and confirms the occurrence of a poly-S-nitrosylation in GST P1-1. S-Nitrosylation of Cys47 lowers the affinity 10-fold for GSH, but this negative effect is minimized by a half-site reactivity mechanism that protects one Cys47/dimer from nitrosylation. Thus, glutathione transferase P1-1, retaining most of its original activity, may act as a NO carrier protein when GSH depletion occurs in the cell. The dinitrosyl-diglutathionyl iron complex, which is formed by S-nitrosoglutathione decomposition in the presence of physiological concentrations of GSH and traces of ferrous ions, binds with extraordinary affinity to one active site of this dimeric enzyme (Ki < 10-12 M) and triggers negative cooperativity in the vacant subunit (Ki = 10-9 M). The complex bound to the enzyme is stable for hours, whereas in the free form and at low concentrations, its life time is only a few minutes. ESR and molecular modeling studies provide a reasonable explanation of this strong interaction, suggesting that Tyr7 and enzyme-bound GSH could be involved in the coordination of the iron atom. All of the observed findings suggest that glutathione transferase P1-1, by means of an intersubunit communication, may act as a NO carrier under different cellular conditions while maintaining its well known detoxificating activity toward dangerous compounds.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b Supported in part by Ministero della Sanità Programma di Ricerca Finalizzato 2000.

e Australian Research Council Senior Research Fellow.

f Wellcome Trust Senior Research Fellow in Medical Science in Australia.

g National Health and Medical Research Council of Australian Industry Fellow.

j Supported in part by the European Training and Mobility of Researchers Programme network "Non-Heme Iron Proteins."

k Supported by Ministero dell'Università e Ricerca Scientifica e Tecnologica Cofin 2000 and the National Research Council of Italy (Target Project on Biotechnology). To whom correspondence should be addressed. Tel.: 39-06-72594379; Fax: 39-06-2025450; E-mail: riccig@uniroma2.it.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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