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J. Biol. Chem., Vol. 279, Issue 19, 19486-19493, May 7, 2004

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Potential Role of Methionine Sulfoxide in the Inactivation of the Chaperone GroEL by Hypochlorous Acid (HOCl) and Peroxynitrite (ONOO^–)^*

Hui Koon Khor, Mark T. Fisher, and Christian Schöneich¶

From the Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047-3729 and the Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas 66160-7421

GroEL is an Escherichia coli molecular chaperone that functions in vivo to fold newly synthesized polypeptides as well as to bind and refold denatured proteins during stress. This protein is a suitable model for its eukaryotic homolog, heat shock protein 60 (Hsp60), due to the high number of conserved amino acid sequences and similar function. Here, we will provide evidence that GroEL is rather insensitive to oxidants produced endogenously during metabolism, such as nitric oxide (·NO) or hydrogen peroxide (H₂O₂), but is modified and inactivated by efficiently reactive species generated by phagocytes, such as peroxynitrite (ONOO^–) and hypochlorous acid (HOCl). For the exposure of 17.5 µM GroEL to 100–250 µM HOCl, the major pathway of inactivation was through the oxidation of methionine to methionine sulfoxide, established through mass spectrometric detection of methionine sulfoxide and the reactivation of a significant fraction of inactivated GroEL by the enzyme methionine sulfoxide reductase B/A (MsrB/A). In addition to the oxidation of methionine, HOCl caused the conversion of cysteine to cysteic acid and this product may account for the remainder of inactivated GroEL not recoverable through MsrB/A. In contrast, HOCl produced only negligible yields of 3-chlorotyrosine. A remarkable finding was the conversion of Met¹¹¹ and Met¹¹⁴ to Met sulfone, which suggests a rather low reduction potential of these 2 residues in GroEL. The high sensitivity of GroEL toward HOCl and ONOO^– suggests that this protein may be a target for bacterial killing by phagocytes.

Received for publication, September 10, 2003 , and in revised form, January 30, 2004.

^* This work was supported by National Institutes of Health Grant AG12993 and by the American Heart Association. 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.

^¶ To whom correspondence should be addressed: Dept. of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Ave., Lawrence, KS 66047-3729. Tel.: 785-864-4880; Fax: 785-864-5736; E-mail: schoneic{at}ku.edu.

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