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J. Biol. Chem., Vol. 278, Issue 43, 42294-42299, October 24, 2003

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Glutathione Transferase Superfamily Behaves Like Storage Proteins for Dinitrosyl-Diglutathionyl-Iron Complex in Heterogeneous Systems^*

Paola Turella, Jens Z. Pedersen¶, Anna Maria Caccuri||**, Francesca De Maria, Piergiorgio Mastroberardino¶, Mario Lo Bello¶||, Giorgio Federici, and Giorgio Ricci||**

From the Department of Chemical Sciences and Technologies and ^¶Department of Biology, University of Rome "Tor Vergata," 00133 Rome and Children's Hospital IRCCS "Bambin Gesù," 00146 Rome, Italy

Electron paramagnetic resonance and kinetics experiments have been made to determine the formation, stability, and fate of the natural nitric oxide carrier, dinitrosyl-diglutathionyl-iron complex (DNDGIC), in heterogeneous systems approaching in vivo conditions. Both in human placenta and rat liver homogenates DNDGIC is formed spontaneously from GSH, S-nitroso-glutathione, and trace amounts of ferrous ions. DNDGIC is unstable in homogenates depleted of glutathione S-transferase (GST); an initial phase of rapid decomposition is followed by a slower decay, which is inversely proportional to the concentration. In the crude human placenta homogenate, GSTP1-1, which represents 90% of the cytosolic GST isoenzymes, is the preferential target for DNDGIC. It binds the complex almost stoichiometrically and stabilizes it for several hours (t_1/2 = 8 h). In the presence of an excess of DNDGIC, negative cooperativity in GSTP1-1 opposes the complete loss of the usual detoxicating activity of this enzyme. In the rat liver homogenate, multiple endogenous GSTs (mainly Alpha and Mu class isoenzymes) bind the complex quantitatively and stabilize it (t_1/2 = 4.5 h); negative cooperativity is also seen for these GSTs. Thus, the entire pool of cytosolic GSTs, with the exception of the Theta GST, represents a target for stoichiometric amounts of DNDGIC and may act as storage proteins for nitric oxide. These results confirm the existence of a cross-link between NO metabolism and the GST superfamily.

Received for publication, May 28, 2003 , and in revised form, July 14, 2003.

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

Both authors contributed equally to this work.

^|| Supported in part by MURST PRIN2002.

^** Supported in part by National Research Council of Italy (Target Project on Biotechnology).

To whom correspondence should be addressed: Dept. of Chemical Sciences and Technologies, University of Rome "Tor Vergata," Via della Ricerca Scientifica, 00133, Rome, Italy. Tel.: 39 0672594379; Fax: 39 0672594311; E-mail: riccig{at}uniroma2.it.

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