Iodotyrosine deiodinase, also known as iodotyrosine dehalogenase 1, is a type of deiodinaseenzyme that scavenges iodide by removing it from iodinated tyrosine residues in the thyroid gland.[1] These iodinated tyrosines are produced during thyroid hormone biosynthesis.[2] The iodide that is scavenged by iodotyrosine deiodinase is necessary to again synthesize the thyroid hormones.[3] After synthesis, the thyroid hormones circulate through the body to regulate metabolic rate, protein expression, and body temperature.[4] Iodotyrosine deiodinase is thus necessary to keep levels of both iodide and thyroid hormones in balance.
Dehalogenation in aerobic organisms is usually done through oxidation and hydrolysis;[5] 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.[4] 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.[6] By contrast, iodotyrosine deiodinase (the topic enzyme) does not require selenocysteine or cysteine for catalysis,[7] is part of the NADH oxidase/flavin reductase superfamily,[8][9] and removes iodide when the substrate is a single amino acid.[10] Research on iodotyrosine deiodinase has historically been variable and slow due to its lack of stability and arduous purification.[11] Only recently has this enzyme been studied more deeply.[4]
The gene encoding this enzyme has been recently identified.[8][9] The sequence of amino acids of iodotyrosine deiodinase is highly conserved among mammals and contains three domains.[4] Iodotyrosine deiodinase is a membrane protein, with the N-terminus functioning as a membrane anchor.[7][13] It forms a dimer that is domain-swapped.[10] Initially, iodotyrosine deiodinase was thought to contain only one flavin mononucleotide (FMN) in each dimer,[14] but now iodotyrosine deiodinase is believed to have two FMN molecules for each homodimer.[10] 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 sites, 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.[10]
Function
Iodotyrosine deiodinase facilitates iodide salvage in the thyroid by catalyzing deiodination of mono- and diiodotyrosine, the halogenated byproducts of thyroid hormone production.[9] Iodide is also an important micronutrient in the biosynthesis of thyroid hormone, creating a cycle of iodide use in the thyroid.[10] 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.[15]
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.[4] Iodotyrosine deiodinase salvages the iodide from the deiodination of the iodinated tyrosines.[16] 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.[10]
The enzymatic activity of iodotyrosine deiodinase has also been known to exist in the tissues of the liver and kidneys as well;[17] however, the physiological significance of these findings is not yet clear.[4]
Mechanism
Iodotyrosine deiodinase catalyzes mono- and diiodotyrosine deiodination. The reaction is NADPH-dependent.[13]Flavin mononucleotide (FMN) is a cofactor.[18] Although flavin is commonly utilized in various catalytic reactions,[19] its use in this reductive dehalogenation is unique and not yet fully understood.[10] 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.[4]
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.[20] Low levels of iodide either through the diet or through iodide metabolism are associated with hypothyroidism, mental retardation, goiter, and developmental defects.[1][4][15] Because iodotyrosine deiodinase is responsible for scavenging iodide, mutations in this enzyme result in iodide deficiency.[21]
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.[22] In some countries, newborn babies are tested for congenital hypothyroidism and treated immediately if the disease is detected, safely preventing the development of mental retardation.[23] However, mutations of iodotyrosine deiodinase are often not detected until after developmental damage has already occurred.[15] Furthermore, these mutations may not be specifically detected using standard thyroid function tests.[15] To combat this issue, a sensitive assay has recently been created that measures the amounts of mono- and diiodotyrosine in the urine.[22]
↑ 1.01.1Moreno JC, Visser TJ (June 2010). "Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations". Molecular and Cellular Endocrinology. 322 (1–2): 91–8. doi:10.1016/j.mce.2010.03.010. PMID20298747.
↑Querido A, Stanbury JB, Kassenaar AA, Meijer JW (August 1956). "The metabolism of iodotyrosines. III. Di-iodotyrosine deshalogenating activity of human thyroid tissue". The Journal of Clinical Endocrinology and Metabolism. 16 (8): 1096–101. doi:10.1210/jcem-16-8-1096. PMID13345866.
↑Häggblom M, Bossert I (2003). Dehalogenation: Microbial Processes and Environmental Applications. Boston: Kluwer Academic Publishers. p. 520. ISBN978-1-4757-7807-6.
↑Callebaut I, Curcio-Morelli C, Mornon JP, Gereben B, Buettner C, Huang S, Castro B, Fonseca TL, Harney JW, Larsen PR, Bianco AC (September 2003). "The iodothyronine selenodeiodinases are thioredoxin-fold family proteins containing a glycoside hydrolase clan GH-A-like structure". The Journal of Biological Chemistry. 278 (38): 36887–96. doi:10.1074/jbc.M305725200. PMID12847093.
↑ 8.08.1Gnidehou S, Caillou B, Talbot M, Ohayon R, Kaniewski J, Noël-Hudson MS, Morand S, Agnangji D, Sezan A, Courtin F, Virion A, Dupuy C (October 2004). "Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site". FASEB Journal. 18 (13): 1574–6. doi:10.1096/fj.04-2023fje. PMID15289438.
↑ 9.09.19.2Friedman JE, Watson JA, Lam DW, Rokita SE (February 2006). "Iodotyrosine deiodinase is the first mammalian member of the NADH oxidase/flavin reductase superfamily". The Journal of Biological Chemistry. 281 (5): 2812–9. doi:10.1074/jbc.M510365200. PMID16316988.
↑Rosenberg IN, Goswami A (December 1979). "Purification and characterization of a flavoprotein from bovine thyroid with iodotyrosine deiodinase activity". The Journal of Biological Chemistry. 254 (24): 12318–25. PMID500717.
↑ 15.015.115.215.3Moreno JC, Klootwijk W, van Toor H, Pinto G, D'Alessandro M, Lèger A, Goudie D, Polak M, Grüters A, Visser TJ (April 2008). "Mutations in the iodotyrosine deiodinase gene and hypothyroidism". The New England Journal of Medicine. 358 (17): 1811–8. doi:10.1056/NEJMoa0706819. PMID18434651.
↑Knobel M, Medeiros-Neto G (August 2003). "An outline of inherited disorders of the thyroid hormone generating system". Thyroid. 13 (8): 771–801. doi:10.1089/105072503768499671. PMID14558921.
↑Choufoer JC, Kassenaar AA, Querido A (July 1960). "The syndrome of congenital hypothyroidism with defective dehalogenation of iodotyrosines. Further observations and a discussion of the pathophysiology". The Journal of Clinical Endocrinology and Metabolism. 20: 983–1003. doi:10.1210/jcem-20-7-983. PMID13810029.
↑Goswami A, Rosenberg IN (December 1979). "Characterization of a flavoprotein iodotyrosine deiodinase from bovine thyroid. Flavin nucleotide binding and oxidation-reduction properties". The Journal of Biological Chemistry. 254 (24): 12326–30. PMID500718.
↑Eastman CJ, Zimmermann M (2000-01-01). De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, Koch C, McLachlan R, New M, eds. The Iodine Deficiency Disorders. South Dartmouth (MA): MDText.com, Inc. PMID25905411.
↑ 22.022.1Afink G, Kulik W, Overmars H, de Randamie J, Veenboer T, van Cruchten A, Craen M, Ris-Stalpers C (December 2008). "Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism". The Journal of Clinical Endocrinology and Metabolism. 93 (12): 4894–901. doi:10.1210/jc.2008-0865. PMID18765512.
↑New England congenital hypothyroidism collaborative (November 1981). "Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations". Lancet. 2 (8255): 1095–8. doi:10.1016/s0140-6736(81)91287-3. PMID6118534.
Further reading
Moreno JC (2003). "Identification of novel genes involved in congenital hypothyroidism using serial analysis of gene expression". Hormone Research. 60 Suppl 3: 96–102. doi:10.1159/000074509. PMID14671405.
Afink G, Kulik W, Overmars H, de Randamie J, Veenboer T, van Cruchten A, Craen M, Ris-Stalpers C (December 2008). "Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism". The Journal of Clinical Endocrinology and Metabolism. 93 (12): 4894–901. doi:10.1210/jc.2008-0865. PMID18765512.
Krause K, Karger S, Gimm O, Sheu SY, Dralle H, Tannapfel A, Schmid KW, Dupuy C, Fuhrer D (March 2007). "Characterisation of DEHAL1 expression in thyroid pathologies". European Journal of Endocrinology / European Federation of Endocrine Societies. 156 (3): 295–301. doi:10.1530/EJE-06-0596. PMID17322488.
Gnidehou S, Lacroix L, Sezan A, Ohayon R, Noël-Hudson MS, Morand S, Francon J, Courtin F, Virion A, Dupuy C (August 2006). "Cloning and characterization of a novel isoform of iodotyrosine dehalogenase 1 (DEHAL1) DEHAL1C from human thyroid: comparisons with DEHAL1 and DEHAL1B". Thyroid. 16 (8): 715–24. doi:10.1089/thy.2006.16.715. PMID16910871.
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 (February 2009). "Genome-wide association study of panic disorder in the Japanese population". Journal of Human Genetics. 54 (2): 122–6. doi:10.1038/jhg.2008.17. PMID19165232.
