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J. Biol. Chem., Vol. 281, Issue 23, 15774-15779, June 9, 2006

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Probes of the Catalytic Site of Cysteine Dioxygenase^*

From the Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01003

The first major step of cysteine catabolism, the oxidation of cysteine to cysteine sulfinic acid, is catalyzed by cysteine dioxygenase (CDO). In the present work, we utilize recombinant rat liver CDO and cysteine derivatives to elucidate structural parameters involved in substrate recognition and x-ray absorption spectroscopy to probe the interaction of the active site iron center with cysteine. Kinetic studies using cysteine structural analogs show that most are inhibitors and that a terminal functional group bearing a negative charge (e.g. a carboxylate) is required for binding. The substrate-binding site has no stringent restrictions with respect to the size of the amino acid. Lack of the amino or carboxyl groups at the -carbon does not prevent the molecules from interacting with the active site. In fact, cysteamine is shown to be a potent activator of the enzyme without being a substrate. CDO was also rendered inactive upon complexation with the metal-binding inhibitors azide and cyanide. Unlike many non-heme iron dioxygenases that employ -keto acids as cofactors, CDO was shown to be the only dioxygenase known to be inhibited by -ketoglutarate.

Received for publication, February 9, 2006 , and in revised form, April 3, 2006.

^* This work was supported by The American Chemical Society Petroleum Research Fund, by the National Institutes of Health-Chemistry Biology Interface Program, Trainee Grant T32 GM08515 (to S. C. C.). 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: Dept. of Chemistry, Lederle Graduate Research Tower, Room 701, University of Massachusetts, 710 North Pleasant St., Amherst, MA 01003. Tel.: 413-545-4876; Fax: 413-545-4490; E-mail: mmaroney{at}chem.umass.edu.

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