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J. Biol. Chem., Vol. 278, Issue 43, 42283-42293, October 24, 2003

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The Specific Interaction of Dinitrosyl-Diglutathionyl-Iron Complex, a Natural NO Carrier, with the Glutathione Transferase Superfamily

SUGGESTION FOR AN EVOLUTIONARY PRESSURE IN THE DIRECTION OF THE STORAGE OF NITRIC OXIDE^*

Francesca De Maria, Jens Z. Pedersen, Anna Maria Caccuri¶||, Giovanni Antonini||**, Paola Turella, Lorenzo Stella, 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, the ^**Department of Biology, University of Rome "Roma Tre," 00146 Rome, and Children's Hospital IRCCS "Bambin Gesù," 00165 Rome, Italy

The interaction of dinitrosyl-diglutathionyl-iron complex (DNDGIC), a natural carrier of nitric oxide, with representative members of the human glutathione transferase (GST) superfamily, i.e. GSTA1-1, GSTM2-2, GSTP1-1, and GSTT2-2, has been investigated by means of pre-steady and steady state kinetics, fluorometry, electron paramagnetic resonance, and radiometric experiments. This complex binds with extraordinary affinity to the active site of all these dimeric enzymes; GSTA1-1 shows the strongest interaction (K_D 10^-10 M), whereas GSTM2-2 and GSTP1-1 display similar and slightly lower affinities (K_D 10^-9 M). Binding of the complex to GSTA1-1 triggers structural intersubunit communication, which lowers the affinity for DNDGIC in the vacant subunit and also causes a drastic loss of enzyme activity. Negative cooperativity is also found in GSTM2-2 and GSTP1-1, but it does not affect the catalytic competence of the second subunit. Stopped-flow and fluorescence data fit well to a common minimal binding mechanism, which includes an initial interaction with GSH and a slower bimolecular interaction of DNDGIC with one high and one low affinity binding site. Interestingly, the Theta class GSTT2-2, close to the ancestral precursor of GSTs, shows very slow binding kinetics and hundred times lowered affinity (K_D 10^-7 M), whereas the bacterial GSTB1-1 is not inhibited by DNDGIC. Molecular modeling and EPR data reveal structural details that may explain the observed kinetic data. The optimized interaction with this NO carrier, developed in the more recently evolved GSTs, may be related to the acquired capacity to utilize NO as a signal messenger.

Received for publication, May 28, 2003 , and in revised form, July 10, 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.

^¶ 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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