View source for Iodotyrosine deiodinase

{{Infobox enzyme
|image =
|caption =
|EC_number = 1.21.1.1
|CAS_number =
|GO_code =
|Name = Iodotyrosine deiodinase
|IUBMB_EC_number = 1/21/1/1
|width =
}}
{{Infobox gene}}

'''Iodotyrosine deiodinase,''' also known as '''iodotyrosine dehalogenase 1,''' is a type of [[deiodinase]] [[enzyme]] that scavenges [[iodide]] by removing it from iodinated [[tyrosine]] residues in the [[thyroid]] gland.<ref name="Moreno_2010"/> These iodinated tyrosines are produced during [[thyroid hormone]] biosynthesis.<ref name="Green_1968"/> The iodide that is scavenged by iodotyrosine deiodinase is necessary to again synthesize the thyroid hormones.<ref name="Querido_1956"/> After synthesis, the thyroid hormones circulate through the body to regulate metabolic rate, protein expression, and body temperature.<ref name="Rokita_2010" /> Iodotyrosine deiodinase is thus necessary to keep levels of both iodide and thyroid hormones in balance.

Dehalogenation in [[aerobic organism]]s is usually done through [[Redox|oxidation]] and [[hydrolysis]];<ref name="Häggblom_2003"/> however, iodotyrosine deiodinase uses reductive dehalogenation. Iodotyrosine deiodinase and [[iodothyronine deiodinase]] have been determined as the only two known enzymes to catalyze reductive dehalogenation in mammals.<ref name="Rokita_2010" />  Although these two enzymes perform similar functions, they are structurally and mechanistically different. [[Iodothyronine deiodinase]] (not the enzyme that is the topic of this article) uses a [[selenocysteine]] active site for catalysis, is a member of the thioredoxin superfamily, and removes iodide only when the substrate is in a double-tyrosine form.<ref name="Callebaut_2003"/> By contrast, iodotyrosine deiodinase (the topic enzyme) does not require [[selenocysteine]] or [[cysteine]] for catalysis,<ref name="Watson_2008"/> is part of the NADH oxidase/flavin reductase superfamily,<ref name="Gnidehou_2004" /><ref name="Friedman_2006" /> and removes iodide when the substrate is a single [[amino acid]].<ref name="Thomas_2009"/> Research on iodotyrosine deiodinase has historically been variable and slow due to its lack of stability and arduous purification.<ref name="Rosenberg_1984"/> Only recently has this enzyme been studied more deeply.<ref name="Rokita_2010" />

== Structure ==
[[File:Protein structure of human iodotyrosine deiodinase .png|thumb|left|Structure of human iodotyrosine deiodinase generated from PDB entry 4TTB.<ref name="PDB_4TTB"/>]]

The [[gene]] encoding this enzyme has been recently identified.<ref name="Gnidehou_2004" /><ref name="Friedman_2006" /> The sequence of amino acids of iodotyrosine deiodinase is highly conserved among [[mammal]]s and contains three domains.<ref name="Rokita_2010" /> Iodotyrosine deiodinase is a [[membrane protein]], with the [[N-terminus]] functioning as a membrane anchor.<ref name="Watson_2008" /><ref name="entrez"/> It forms a [[Dimer (biochemistry)|dimer]] that is domain-swapped.<ref name="Thomas_2009" /> Initially, iodotyrosine deiodinase was thought to contain only one [[flavin mononucleotide]] (FMN) in each dimer,<ref name="Rosenberg_1979"/> but now iodotyrosine deiodinase is believed to have two FMN molecules for each homodimer.<ref name="Thomas_2009" /> The enzyme has a characteristic α-β fold that all proteins from the NADH oxidase/flavin reductase superfamily have as well. Within the dimer interface, there are two equivalent [[active site]]s, each made from residues from both subunits. Thus, subunit association must be required for FMN binding and catalysis. Substrate binding causes a conformational change in the enzyme in order to close the active site, protecting the substrate and flavin from the solvent.<ref name="Thomas_2009" />
{{clear|left}}

== Function ==
Iodotyrosine deiodinase facilitates iodide salvage in the thyroid by catalyzing deiodination of [[monoiodotyrosine|mono]]- and [[diiodotyrosine]], the halogenated byproducts of [[thyroid hormone]] production.<ref name="Friedman_2006" /> Iodide is also an important micronutrient in the biosynthesis of thyroid hormone, creating a cycle of iodide use in the thyroid.<ref name="Thomas_2009" /> Iodide [[homeostasis]] within the thyroid gland is essential for producing thyroid hormone at appropriate rates. Thus, iodide levels must be regulated in order to keep thyroid hormones, and ultimately the organism's metabolic rate and overall health, in good status.<ref name="Moreno_2008" />

Within the thyroid follicular cell, [[thyroglobulin]] is hydrolyzed to form thyroid hormones and mono- and diiodotyrosine. The thyroid hormones are released into the bloodstream and the iodinated tyrosines are recycled. However, the breakdown of thyroglobulin produces 6-7 fold more iodinated tyrosines than thyroid hormone.<ref name="Rokita_2010" />  Iodotyrosine deiodinase salvages the iodide from the deiodination of the iodinated tyrosines.<ref name="Knobel_2003"/> Iodotyrosine deiodinase is located on the apical plasma membrane of the thyroid colloid, where mono- and diiodotyrosine are produced from this breakdown of thyroglobulin. Without iodotyrosine deiodinase activity, the iodide would be excreted with the amino acid tyrosine and thyroid hormone biosynthesis would be reduced.<ref name="Thomas_2009" />

The enzymatic activity of iodotyrosine deiodinase has also been known to exist in the tissues of the liver and kidneys as well;<ref name="Choufoer_1960" /> however, the physiological significance of these findings is not yet clear.<ref name="Rokita_2010" />

== Mechanism ==
Iodotyrosine deiodinase catalyzes mono- and diiodotyrosine deiodination. The reaction is [[Nicotinamide adenine dinucleotide phosphate|NADPH]]-dependent.<ref name="entrez"/>  [[Flavin mononucleotide]] (FMN) is a cofactor.<ref name="Goswami_1979"/> Although flavin is commonly utilized in various catalytic reactions,<ref name="Mansoorabadi_2007"/> its use in this reductive dehalogenation is unique and not yet fully understood.<ref name="Thomas_2009" /> It is also still unclear if the enzyme mechanism utilizes a two electron transfer reaction or a series of one electron transfers. Although further research must be done to determine details of this mechanism, recent evidence seems to suggest that iodotyrosine deiodinase acts through one electron transfer reactions.<ref name="Rokita_2010" />
[[File:Iodotyrosine deiodinase reaction 2.png|none|thumb|600x600px|Iodotyrosine deiodinase reaction scheme.<ref name="Rokita_2010"/>]]

== Clinical significance ==
Mutations in the gene encoding iodotyrosine deiodinase can affect enzyme function and be detrimental to human health. Iodide is an essential micronutrient for health in mammals.<ref name="Eastman_2000"/> Low levels of iodide either through the diet or through iodide metabolism are associated with [[hypothyroidism]], mental retardation, [[Goitre|goiter]], and developmental defects.<ref name="Moreno_2010" /><ref name="Rokita_2010" /><ref name="Moreno_2008"/> Because iodotyrosine deiodinase is responsible for scavenging iodide, mutations in this enzyme result in iodide deficiency.<ref name="Lever_1983" />

The resulting high blood and [[urine]] concentrations of iodotyrosine can be used as a measure for diagnosis, as the iodide is not removed from the tyrosine residues effectively.<ref name="Afink_2008"/> In some countries, newborn babies are tested for [[Congenital disorder|congenital]] hypothyroidism and treated immediately if the disease is detected, safely preventing the development of mental retardation.<ref name="NEchc_1981"/> However, mutations of iodotyrosine deiodinase are often not detected until after developmental damage has already occurred.<ref name="Moreno_2008" /> Furthermore, these mutations may not be specifically detected using standard thyroid function tests.<ref name="Moreno_2008" /> To combat this issue, a sensitive assay has recently been created that measures the amounts of mono- and diiodotyrosine in the urine.<ref name="Afink_2008" />

== See also ==
* [[Thyroid peroxidase]]
* [[Iodotyrosine]]
* [[Iodothyronine deiodinase]]

== References ==
{{reflist|33em|refs =

<ref name = "Afink_2008">{{cite journal | vauthors = Afink G, Kulik W, Overmars H, de Randamie J, Veenboer T, van Cruchten A, Craen M, Ris-Stalpers C | title = Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 12 | pages = 4894–901 | date = December 2008 | pmid = 18765512 | doi = 10.1210/jc.2008-0865 }}</ref>

<ref name = "Callebaut_2003">{{cite journal | vauthors = Callebaut I, Curcio-Morelli C, Mornon JP, Gereben B, Buettner C, Huang S, Castro B, Fonseca TL, Harney JW, Larsen PR, Bianco AC | title = The iodothyronine selenodeiodinases are thioredoxin-fold family proteins containing a glycoside hydrolase clan GH-A-like structure | journal = The Journal of Biological Chemistry | volume = 278 | issue = 38 | pages = 36887–96 | date = September 2003 | pmid = 12847093 | doi = 10.1074/jbc.M305725200 }}</ref>

<ref name = "Choufoer_1960">{{cite journal | vauthors = Choufoer JC, Kassenaar AA, Querido A | title = The syndrome of congenital hypothyroidism with defective dehalogenation of iodotyrosines. Further observations and a discussion of the pathophysiology | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 20 | pages = 983–1003 | date = July 1960 | pmid = 13810029 | doi = 10.1210/jcem-20-7-983 }}</ref>

<ref name = "Eastman_2000">{{cite book | url = https://www.ncbi.nlm.nih.gov/books/NBK285556/ | title = The Iodine Deficiency Disorders | last = Eastman | first = Creswell J. | last2 = Zimmermann | first2 = Michael | name-list-format = vanc | date = 2000-01-01 | publisher = MDText.com, Inc. | editor-last = De Groot | editor-first = Leslie J. | location = South Dartmouth (MA) | pmid = 25905411 | editor-last2 = Beck-Peccoz | editor-first2 = Paolo | editor-last3 = Chrousos | editor-first3 = George | editor-last4 = Dungan | editor-first4 = Kathleen | editor-last5 = Grossman | editor-first5 = Ashley | editor-last6 = Hershman | editor-first6 = Jerome M. | editor-last7 = Koch | editor-first7 = Christian | editor-last8 = McLachlan | editor-first8 = Robert | editor-last9 = New | editor-first9 = Maria }}</ref>

<ref name = "entrez">{{cite web | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=389434 | title = Entrez Gene: IYD Iodotyrosine deiodinase | publisher = United States National Library of Medicine | work = Entrez Gene }}</ref>

<ref name = "Friedman_2006">{{cite journal | vauthors = Friedman JE, Watson JA, Lam DW, Rokita SE | title = Iodotyrosine deiodinase is the first mammalian member of the NADH oxidase/flavin reductase superfamily | journal = The Journal of Biological Chemistry | volume = 281 | issue = 5 | pages = 2812–9 | date = February 2006 | pmid = 16316988 | doi = 10.1074/jbc.M510365200 }}</ref>

<ref name = "Gnidehou_2004">{{cite journal | vauthors = Gnidehou S, Caillou B, Talbot M, Ohayon R, Kaniewski J, Noël-Hudson MS, Morand S, Agnangji D, Sezan A, Courtin F, Virion A, Dupuy C | title = Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site | journal = FASEB Journal | volume = 18 | issue = 13 | pages = 1574–6 | date = October 2004 | pmid = 15289438 | doi = 10.1096/fj.04-2023fje }}</ref>

<ref name = "Goswami_1979">{{cite journal | vauthors = Goswami A, Rosenberg IN | title = Characterization of a flavoprotein iodotyrosine deiodinase from bovine thyroid. Flavin nucleotide binding and oxidation-reduction properties | journal = The Journal of Biological Chemistry | volume = 254 | issue = 24 | pages = 12326–30 | date = December 1979 | pmid = 500718 }}</ref>

<ref name = "Green_1968">{{cite journal | vauthors = Green WL | title = Inhibition of thyroidal iodotyrosine deiodination by tyrosine analogues | journal = Endocrinology | volume = 83 | issue = 2 | pages = 336–47 | date = August 1968 | pmid = 5668272 | doi = 10.1210/endo-83-2-336 | url = http://press.endocrine.org/doi/pdf/10.1210/endo-83-2-336 }}</ref>

<ref name = "Häggblom_2003">{{cite book | title = Dehalogenation: Microbial Processes and Environmental Applications | last = Häggblom | first = M.M. | last2 = Bossert | first2 = I.D. | name-list-format = vanc | publisher = Kluwer Academic Publishers | year = 2003 | isbn = 978-1-4757-7807-6 | location = Boston | pages = 520 }}</ref>

<ref name = "Knobel_2003">{{cite journal | vauthors = Knobel M, Medeiros-Neto G | title = An outline of inherited disorders of the thyroid hormone generating system | journal = Thyroid | volume = 13 | issue = 8 | pages = 771–801 | date = August 2003 | pmid = 14558921 | doi = 10.1089/105072503768499671 }}</ref>

<ref name = "Lever_1983">{{cite journal | vauthors = Lever EG, Medeiros-Neto GA, DeGroot LJ | title = Inherited disorders of thyroid metabolism | journal = Endocrine Reviews | date = 1983 | volume = 4 | issue = 3 | pages = 213–39 | pmid = 6354701 | doi = 10.1210/edrv-4-3-213 | url = http://press.endocrine.org/doi/pdf/10.1210/edrv-4-3-213 }}</ref>

<ref name = "Mansoorabadi_2007">{{cite journal | vauthors = Mansoorabadi SO, Thibodeaux CJ, Liu HW | title = The diverse roles of flavin coenzymes--nature's most versatile thespians | journal = The Journal of Organic Chemistry | volume = 72 | issue = 17 | pages = 6329–42 | date = August 2007 | pmid = 17580897 | pmc = 2519020 | doi = 10.1021/jo0703092 }}</ref>

<ref name = "Moreno_2008">{{cite journal | vauthors = Moreno JC, Klootwijk W, van Toor H, Pinto G, D'Alessandro M, Lèger A, Goudie D, Polak M, Grüters A, Visser TJ | title = Mutations in the iodotyrosine deiodinase gene and hypothyroidism | journal = The New England Journal of Medicine | volume = 358 | issue = 17 | pages = 1811–8 | date = April 2008 | pmid = 18434651 | doi = 10.1056/NEJMoa0706819 }}</ref>

<ref name = "Moreno_2010">{{cite journal | vauthors = Moreno JC, Visser TJ | title = Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations | journal = Molecular and Cellular Endocrinology | volume = 322 | issue = 1-2 | pages = 91–8 | date = June 2010 | pmid = 20298747 | doi = 10.1016/j.mce.2010.03.010 }}</ref>

<ref name = "NEchc_1981">{{cite journal | vauthors = ((New England congenital hypothyroidism collaborative)) | title = Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations.  | journal = Lancet | volume = 2 | issue = 8255 | pages = 1095–8 | date = November 1981 | pmid = 6118534 | doi =  10.1016/s0140-6736(81)91287-3}}<!--| access-date = 29 February 2016 --></ref>

<ref name = "PDB_4TTB">{{Cite web | url = http://www.rcsb.org/pdb/results/results.do?outformat=&qrid=B331BDE0&tabtoshow=Current | title = RCSB PDB - Search Results | publisher = RCSB Protein Data Banck | website = www.rcsb.org | access-date = 2016-03-01 }}</ref>

<ref name = "Querido_1956">{{cite journal | vauthors = Querido A, Stanbury JB, Kassenaar AA, Meijer JW | title = The metabolism of iodotyrosines. III. Di-iodotyrosine deshalogenating activity of human thyroid tissue | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 16 | issue = 8 | pages = 1096–101 | date = August 1956 | pmid = 13345866 | doi = 10.1210/jcem-16-8-1096 }}</ref>

<ref name = "Rokita_2010">{{cite journal | vauthors = Rokita SE, Adler JM, McTamney PM, Watson JA | title = Efficient use and recycling of the micronutrient iodide in mammals | journal = Biochimie | volume = 92 | issue = 9 | pages = 1227–35 | date = September 2010 | pmid = 20167242 | pmc = 2888766 | doi = 10.1016/j.biochi.2010.02.013 }}</ref>

<ref name = "Rosenberg_1979">{{cite journal | vauthors = Rosenberg IN, Goswami A | title = Purification and characterization of a flavoprotein from bovine thyroid with iodotyrosine deiodinase activity | journal = The Journal of Biological Chemistry | volume = 254 | issue = 24 | pages = 12318–25 | date = December 1979 | pmid = 500717 }}</ref>

<ref name = "Rosenberg_1984">{{cite journal | vauthors = Rosenberg IN, Goswami A | title = Iodotyrosine deiodinase from bovine thyroid | journal = Methods in Enzymology | volume = 107 | pages = 488–500 | date = 1984-01-01 | pmid = 6503724 | doi = 10.1016/0076-6879(84)07033-6 }}</ref>

<ref name = "Thomas_2009">{{cite journal | vauthors = Thomas SR, McTamney PM, Adler JM, Laronde-Leblanc N, Rokita SE | title = Crystal structure of iodotyrosine deiodinase, a novel flavoprotein responsible for iodide salvage in thyroid glands | journal = The Journal of Biological Chemistry | volume = 284 | issue = 29 | pages = 19659–67 | date = July 2009 | pmid = 19436071 | pmc = 2740591 | doi = 10.1074/jbc.M109.013458 }}</ref>

<ref name = "Watson_2008">{{cite journal | vauthors = Watson JA, McTamney PM, Adler JM, Rokita SE | title = Flavoprotein iodotyrosine deiodinase functions without cysteine residues | journal = Chembiochem | volume = 9 | issue = 4 | pages = 504–6 | date = March 2008 | pmid = 18228228 | doi = 10.1002/cbic.200700562 }}</ref>

}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Moreno JC | title = Identification of novel genes involved in congenital hypothyroidism using serial analysis of gene expression | journal = Hormone Research | volume = 60 Suppl 3 | issue =  | pages = 96–102 | year = 2003 | pmid = 14671405 | doi = 10.1159/000074509 }}
* {{cite journal | vauthors = Afink G, Kulik W, Overmars H, de Randamie J, Veenboer T, van Cruchten A, Craen M, Ris-Stalpers C | title = Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 93 | issue = 12 | pages = 4894–901 | date = December 2008 | pmid = 18765512 | doi = 10.1210/jc.2008-0865 }}
* {{cite journal | vauthors = Gieger C, Geistlinger L, Altmaier E, Hrabé de Angelis M, Kronenberg F, Meitinger T, Mewes HW, Wichmann HE, Weinberger KM, Adamski J, Illig T, Suhre K | title = Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum | journal = PLoS Genetics | volume = 4 | issue = 11 | pages = e1000282 | date = November 2008 | pmid = 19043545 | pmc = 2581785 | doi = 10.1371/journal.pgen.1000282 | editor1-last = Gibson | editor1-first = Greg }}
* {{cite journal | vauthors = Thomas SR, McTamney PM, Adler JM, Laronde-Leblanc N, Rokita SE | title = Crystal structure of iodotyrosine deiodinase, a novel flavoprotein responsible for iodide salvage in thyroid glands | journal = The Journal of Biological Chemistry | volume = 284 | issue = 29 | pages = 19659–67 | date = July 2009 | pmid = 19436071 | pmc = 2740591 | doi = 10.1074/jbc.M109.013458 }}
* {{cite journal | vauthors = Krause K, Karger S, Gimm O, Sheu SY, Dralle H, Tannapfel A, Schmid KW, Dupuy C, Fuhrer D | title = Characterisation of DEHAL1 expression in thyroid pathologies | journal = European Journal of Endocrinology / European Federation of Endocrine Societies | volume = 156 | issue = 3 | pages = 295–301 | date = March 2007 | pmid = 17322488 | doi = 10.1530/EJE-06-0596 }}
* {{cite journal | vauthors = Gnidehou S, Lacroix L, Sezan A, Ohayon R, Noël-Hudson MS, Morand S, Francon J, Courtin F, Virion A, Dupuy C | title = Cloning and characterization of a novel isoform of iodotyrosine dehalogenase 1 (DEHAL1) DEHAL1C from human thyroid: comparisons with DEHAL1 and DEHAL1B | journal = Thyroid | volume = 16 | issue = 8 | pages = 715–24 | date = August 2006 | pmid = 16910871 | doi = 10.1089/thy.2006.16.715 }}
* {{cite journal | vauthors = Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, Tochigi M, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Tanii H, Sasaki T, Kaiya H, Okazaki Y | title = Genome-wide association study of panic disorder in the Japanese population | journal = Journal of Human Genetics | volume = 54 | issue = 2 | pages = 122–6 | date = February 2009 | pmid = 19165232 | doi = 10.1038/jhg.2008.17 }}
{{refend}}

== External links ==
* {{MeshName|Iodotyrosine+Deiodinase}}

{{Thyroid hormone metabolism enzymes and transporters}}
{{Other oxidoreductases}}
{{Enzymes}}
{{Portal bar|Molecular and Cellular Biology|border=no}}

{{NLM content}}
{{Use dmy dates|date=April 2017}}

[[Category:EC 1.21.1]]