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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Sechi, Salvatore
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Maryland College Park
Schools of Earth Sciences/Natur
College Park
United States
Zip Code
Sun, Zuodong; Su, Qi; Rokita, Steven E (2017) The distribution and mechanism of iodotyrosine deiodinase defied expectations. Arch Biochem Biophys 632:77-87
Bobyk, Kostyantyn D; Ballou, David P; Rokita, Steven E (2015) Rapid kinetics of dehalogenation promoted by iodotyrosine deiodinase from human thyroid. Biochemistry 54:4487-94
Hu, Jimin; Chuenchor, Watchalee; Rokita, Steven E (2015) A switch between one- and two-electron chemistry of the human flavoprotein iodotyrosine deiodinase is controlled by substrate. J Biol Chem 290:590-600
Mukherjee, Arnab; Rokita, Steven E (2015) Single Amino Acid Switch between a Flavin-Dependent Dehalogenase and Nitroreductase. J Am Chem Soc 137:15342-5
Phatarphekar, Abhishek; Buss, Jennifer M; Rokita, Steven E (2014) Iodotyrosine deiodinase: a unique flavoprotein present in organisms of diverse phyla. Mol Biosyst 10:86-92
Buss, Jennifer M; McTamney, Patrick M; Rokita, Steven E (2012) Expression of a soluble form of iodotyrosine deiodinase for active site characterization by engineering the native membrane protein from Mus musculus. Protein Sci 21:351-61
Rokita, Steven E; Adler, Jennifer M; McTamney, Patrick M et al. (2010) Efficient use and recycling of the micronutrient iodide in mammals. Biochimie 92:1227-35
McTamney, Patrick M; Rokita, Steven E (2009) A mammalian reductive deiodinase has broad power to dehalogenate chlorinated and brominated substrates. J Am Chem Soc 131:14212-3