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J. Biol. Chem., Vol. 280, Issue 49, 40684-40698, December 9, 2005

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Intramolecular Electron Transfer between Tyrosyl Radical and Cysteine Residue Inhibits Tyrosine Nitration and Induces Thiyl Radical Formation in Model Peptides Treated with Myeloperoxidase, H₂O₂, and NO₂^-

EPR SPIN TRAPPING STUDIES^*

From the Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

We investigated the effects of a cysteine residue on tyrosine nitration in several model peptides treated with myeloperoxidase (MPO), H₂O₂, and nitrite anion () and with horseradish peroxidase and H₂O₂. Sequences of model peptides were acetyl-Tyr-Cys-amide (YC), acetyl-Tyr-Ala-Cys-amide (YAC), acetyl-Tyr-Ala-Ala-Cys-amide (YAAC), and acetyl-Tyr-Ala-Ala-Ala-Ala-Cys-amide (YAAAAC). Results indicate that nitration and oxidation products of tyrosyl residue in YC and other model peptides were barely detectable. A major product detected was the corresponding disulfide (e.g. YCysCysY). Spin trapping experiments with 5,5'-dimethyl-1-pyrroline N-oxide (DMPO) revealed thiyl adduct (e.g. DMPO-SCys-Tyr) formation from peptides (e.g. YC) treated with MPO/H₂O₂ and . The steady-state concentrations of DMPO-thiyl adducts decreased with increasing chain length of model peptides. Blocking the sulfydryl group in YC with methylmethanethiosulfonate (that formed YCSSCH₃) totally inhibited thiyl radical formation as did substitution of Tyr with Phe (i.e. FC) in the presence of . However, increased tyrosine nitration, tyrosine dimerization, and tyrosyl radical formation were detected in the system. Increased formation of S-nitrosated YC (YCysNO) was detected in the MPO/H₂O₂/^·NO system. We conclude that a rapid intramolecular electron transfer reaction between the tyrosyl radical and the Cys residue impedes tyrosine nitration and induces corresponding thiyl radical and nitrosocysteine product. Implications of this novel intramolecular electron transfer mechanism in protein nitration and nitrosation are discussed.

Received for publication, April 25, 2005 , and in revised form, September 19, 2005.

^* This work was supported by National Institutes of Health Grant HL63119. 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1S and 2S.

¹ To whom correspondence should be addressed: Dept. of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Rd., P.O. Box 26509, Milwaukee, WI 53226. Tel.: 414-456-4035; Fax: 414-456-6512; E-mail: balarama{at}mcw.edu.

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