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J. Biol. Chem., Vol. 281, Issue 5, 2812-2819, February 3, 2006

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Iodotyrosine Deiodinase Is the First Mammalian Member of the NADH Oxidase/Flavin Reductase Superfamily^*

From the Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742

The enzyme responsible for iodide salvage in the thyroid, iodotyrosine deiodinase, was solubilized from porcine thyroid microsomes by limited proteolysis with trypsin. The resulting protein retained deiodinase activity and was purified using anion exchange, dye, and hydrophobic chromatography successively. Peptide sequencing of the final isolate identified the gene responsible for the deiodinase. The amino acid sequence of the porcine enzyme is highly homologous to corresponding genes in a variety of mammals including humans, and the mouse gene was expressed in human embryonic kidney 293 cells to confirm its identity. The amino acid sequence of the deiodinase suggests the presence of three domains. The N-terminal domain provides a membrane anchor. The intermediate domain contains the highest sequence variability and lacks homology to structural motifs available in the common databases. The C-terminal domain is highly conserved and resembles bacterial enzymes of the NADH oxidase/flavin reductase superfamily. A three-dimensional model of the deiodinase based on the coordinates of the minor nitroreductase of Escherichia coli indicates that a Cys common to all of the mammal sequences is located adjacent to bound FMN. However, the deiodinase is not structurally related to other known flavoproteins containing redox-active cysteines or the iodothyronine deiodinases containing an active site selenocysteine.

Received for publication, September 21, 2005 , and in revised form, November 7, 2005.

^* 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 Current address: Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142.

² Supported in part by Howard Hughes Medical Institute through the Undergraduate Biological Sciences Education Program.

³ To whom correspondence should be addressed. Tel.: 301-405-1816; Fax: 301-405-9376; E-mail: rokita{at}umd.edu.

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