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J. Biol. Chem., Vol. 282, Issue 5, 3391-3402, February 2, 2007

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An Insight into the Mechanism of Human Cysteine Dioxygenase

KEY ROLES OF THE THIOETHER-BONDED TYROSINE-CYSTEINE COFACTOR^*

From the Tsinghua-IBP Joint Research Group for Structural Biology, Tsinghua University, Beijing 100084 and the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

Cysteine dioxygenase is a non-heme mononuclear iron metalloenzyme that catalyzes the oxidation of cysteine to cysteine sulfinic acid with addition of molecular dioxygen. This irreversible oxidative catabolism of cysteine initiates several important metabolic pathways related to diverse sulfurate compounds. Cysteine dioxygenase is therefore very important for maintaining the proper hepatic concentration of intracellular free cysteine. Mechanisms for mouse and rat cysteine dioxygenases have recently been reported based on their crystal structures in the absence of substrates, although there is still a lack of direct evidence. Here we report the first crystal structure of human cysteine dioxygenase in complex with its substrate L-cysteine to 2.7Å, together with enzymatic activity and metal content assays of several single point mutants. Our results provide an insight into a new mechanism of cysteine thiol dioxygenation catalyzed by cysteine dioxygenase, which is tightly associated with a thioether-bonded tyrosine-cysteine cofactor involving Tyr-157 and Cys-93. This cross-linked protein-derived cofactor plays several key roles different from those in galactose oxidase. This report provides a new potential target for therapy of diseases related to human cysteine dioxygenase, including neurodegenerative and autoimmune diseases.

Received for publication, October 3, 2006 , and in revised form, November 13, 2006.

The atomic coordinates and structure factors (code 2IC1) 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 the Ministry of Science & Technology Human Liver Proteomics Project (Grant 2004CB520801) and the National Natural Science Foundation of China (Grants 30221003 and 30370295). 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 should be addressed. Tel.: 86-10-6277-1493; Fax: 86-10-6277-3145; E-mail: raozh{at}xtal.tsinghua.edu.cn.

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