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J. Biol. Chem., Vol. 281, Issue 27, 18723-18733, July 7, 2006

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Crystal Structure of Mammalian Cysteine Dioxygenase

A NOVEL MONONUCLEAR IRON CENTER FOR CYSTEINE THIOL OXIDATION^*

Chad R. Simmons, Qun Liu, Qingqiu Huang, Quan Hao, Tadhg P. Begley^¶, P. Andrew Karplus^||1, and Martha H. Stipanuk²

From the Division of Nutritional Sciences, Macromolecular Diffraction Facility at Cornell High Energy Synchrotron Source (MacCHESS), and the ^¶Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-8001 and the ^||Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331-4501

Cysteine dioxygenase is a mononuclear iron-dependent enzyme responsible for the oxidation of cysteine with molecular oxygen to form cysteine sulfinate. This reaction commits cysteine to either catabolism to sulfate and pyruvate or the taurine biosynthetic pathway. Cysteine dioxygenase is a member of the cupin superfamily of proteins. The crystal structure of recombinant rat cysteine dioxygenase has been determined to 1.5-Å resolution, and these results confirm the canonical cupin -sandwich fold and the rare cysteinyltyrosine intramolecular cross-link (between Cys⁹³ and Tyr¹⁵⁷) seen in the recently reported murine cysteine dioxygenase structure. In contrast to the catalytically inactive mononuclear Ni(II) metallocenter present in the murine structure, crystallization of a catalytically competent preparation of rat cysteine dioxygenase revealed a novel tetrahedrally coordinated mononuclear iron center involving three histidines (His⁸⁶, His⁸⁸, and His¹⁴⁰) and a water molecule. Attempts to acquire a structure with bound ligand using either cocrystallization or soaking crystals with cysteine revealed the formation of a mixed disulfide involving Cys¹⁶⁴ near the active site, which may explain previously observed substrate inhibition. This work provides a framework for understanding the molecular mechanisms involved in thiol dioxygenation and sets the stage for exploration of the chemistry of both the novel mononuclear iron center and the catalytic role of the cysteinyl-tyrosine linkage.

Received for publication, February 17, 2006 , and in revised form, March 30, 2006.

The atomic coordinates and structure factors (code 2B5H and 2GH2) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grants PHS DK056649 (to M. H. S.), PHS DK044083 (to T. P. B.) and RR-01646 (to Q. H.). 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.

¹ To whom correspondence may be addressed: Dept. of Biochemistry and Biophysics, Oregon State University, 2011 Ag. & Life Sciences Bldg., Corvallis, OR 97331. Tel.: 541-737-3200; Fax: 541-737-0481; E-mail: karplusp{at}science.oregonstate.edu. ² To whom correspondence may be addressed: Div. of Nutritional Sciences, Cornell University, 227 Savage Hall, Ithaca, NY 14853. Tel.: 607-255-2683; Fax: 607-255-1033; E-mail: mhs6{at}cornell.edu.

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