Reductive Dehalogenation in Mammals by Iodotyrosine Deiodinase
Principal Investigator: Steven E Rokita
Abstract: Organohalides are ubiquitous in the environment through natural and human activities. Most organisms detoxify and degrade these compounds by enzyme-mediated hydrolysis, elimination or oxidation. Certain microbes are also capable of promoting reductive dehalogenation, although this is primarily limited to anaerobic metabolism. Mammals provide a fascinating exception to this general observation. The essential hormone, thyroxine (3-[4-[4-hydroxy-3,5-diiodophenoxy]-3,5-diiodophenyl]alanine), is reductively deiodinated in a variety of tissues by selenocysteine-containing enzymes. Quite surprisingly, an entirely different strategy has been recruited in the thyroid to deiodinate 3-iodo- and 3,5-diiodotyrosine. In this case, a unique flavoprotein, iodotyrosine deiodinase, is responsible for reducing the iodinated amino acids in order to salvage iodide for reuse in thyroxine biosynthesis. Investigations are now proposed to identify the unprecedented chemistry and mechanism of this mammalian deiodinase. The novel properties of this enzyme will extend the known repertoire of flavin-dependent catalysis and pathways available in biology to process halogenated compounds. Our description of catalysis will focus on the reduction of the C-I bond and concomitant oxidation of the reduced flavin in IYD. Spectroscopic and product analyses will be used to differentiate between one and two electron processes and, for the first time, reveal the full range of substrates that are processed by IYD. Activation of both the substrate and flavin cofactor will be described by independently measuring recognition and catalytic properties of enzyme mutants and substrate analogues. Concurrently, substrate-dependent control of the flavin chemistry will be detected by changes in its redox properties. These investigations will be enriched as well by continuing crystallographic studies of IYD. Finally, the origins of this unusual deiodination will be examined by expressing and characterizing homologous genes from organisms that are successively more distant from mammals in the "Tree of Life." PUBLIC HEALTH RELEVANCE: Iodide is a necessary component of our diet and used to produce an iodide-containing hormone in the thyroid that is required for regulating the metabolic rate of our entire body. The process by which we recycle iodide from byproducts formed during hormone biosynthesis will be investigated and is crucial to understand the basis for certain congenital defects leading to hypothyroidism.
Funding Period: -------------------- - --------------------
more information: NIH RePORT
- A mammalian reductive deiodinase has broad power to dehalogenate chlorinated and brominated substratesPatrick M McTamney
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, USA
J Am Chem Soc 131:14212-3. 2009..These new activities expand the possible roles of flavin in biological catalysis and provide a foundation for determining the mechanism of this unusual process...
- Efficient use and recycling of the micronutrient iodide in mammalsSteven E Rokita
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
Biochimie 92:1227-35. 2010..The structure of an enzyme.substrate co-crystal has become invaluable for understanding the origins of substrate selectivity and the mutations causing thyroid disease in humans...
- Expression of a soluble form of iodotyrosine deiodinase for active site characterization by engineering the native membrane protein from Mus musculusJennifer M Buss
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742 2021, USA
Protein Sci 21:351-61. 2012..This final construct provided abundant enzyme for crystallography and mutagenesis. Utility of the E. coli system was demonstrated by examining a set of active site residues critical for binding to the zwitterionic portion of substrate...
- Iodotyrosine deiodinase: a unique flavoprotein present in organisms of diverse phylaAbhishek Phatarphekar
Department of Chemistry, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA
Mol Biosyst 10:86-92. 2014..At least for Metazoa, IYD should provide a new marker for tracing the evolutionary development of iodinated amino acids as regulatory signals through the tree of life. ..