Iodotyrosine deiodinase

Last updated
Iodotyrosine deiodinase
Identifiers
EC no. 1.21.1.1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Search
PMC articles
PubMed articles
NCBI proteins
IYD
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IYD , iodotyrosine deiodinase, C6orf71, DEHAL1, TDH4, dJ422F24.1, IYD-1
External IDs OMIM: 612025 MGI: 1917587 HomoloGene: 12352 GeneCards: IYD
Orthologs
SpeciesHumanMouse
Entrez

389434

70337

Ensembl

ENSG00000009765

ENSMUSG00000019762

UniProt

Q6PHW0

Q9DCX8

RefSeq (mRNA)

NM_001164694
NM_001164695
NM_203395
NM_001318495

NM_027391

RefSeq (protein)

NP_001158166
NP_001158167
NP_001305424
NP_981932

NP_081667

Location (UCSC) Chr 6: 150.37 – 150.41 Mb Chr 10: 3.49 – 3.5 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] These iodinated tyrosines are produced during thyroid hormone biosynthesis. [6] The iodide that is scavenged by iodotyrosine deiodinase is necessary to again synthesize the thyroid hormones. [7] After synthesis, the thyroid hormones circulate through the body to regulate metabolic rate, protein expression, and body temperature. [8] Iodotyrosine deiodinase is thus necessary to keep levels of both iodide and thyroid hormones in balance.

Contents

Dehalogenation in aerobic organisms is usually done through oxidation and hydrolysis; [9] 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. [8] 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. [10] By contrast, iodotyrosine deiodinase (the topic enzyme) does not require selenocysteine or cysteine for catalysis, [11] is part of the NADH oxidase/flavin reductase superfamily, [12] [13] and removes iodide when the substrate is a single amino acid. [14] Research on iodotyrosine deiodinase has historically been variable and slow due to its lack of stability and arduous purification. [15] Only recently has this enzyme been studied more deeply. [8]

Structure

Structure of human iodotyrosine deiodinase generated from PDB entry 4TTB. Protein structure of human iodotyrosine deiodinase .png
Structure of human iodotyrosine deiodinase generated from PDB entry 4TTB.

The gene encoding this enzyme has been recently identified. [12] [13] The sequence of amino acids of iodotyrosine deiodinase is highly conserved among mammals and contains three domains. [8] Iodotyrosine deiodinase is a membrane protein, with the N-terminus functioning as a membrane anchor. [11] [17] It forms a dimer that is domain-swapped. [14] Initially, iodotyrosine deiodinase was thought to contain only one flavin mononucleotide (FMN) in each dimer, [18] but now iodotyrosine deiodinase is believed to have two FMN molecules for each homodimer. [14] 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. [14]

Function

Iodotyrosine deiodinase facilitates iodide salvage in the thyroid by catalyzing deiodination of mono- and diiodotyrosine, the halogenated byproducts of thyroid hormone production. [13] Iodide is also an important micronutrient in the biosynthesis of thyroid hormone, creating a cycle of iodide use in the thyroid. [14] 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. [19]

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. [8] Iodotyrosine deiodinase salvages the iodide from the deiodination of the iodinated tyrosines. [20] 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. [14]

The enzymatic activity of iodotyrosine deiodinase has also been known to exist in the tissues of the liver and kidneys as well; [21] however, the physiological significance of these findings is not yet clear. [8]

Mechanism

Iodotyrosine deiodinase catalyzes mono- and diiodotyrosine deiodination. The reaction is NADPH-dependent. [17] Flavin mononucleotide (FMN) is a cofactor. [22] Although flavin is commonly utilized in various catalytic reactions, [23] its use in this reductive dehalogenation is unique and not yet fully understood. [14] 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. [8]

Iodotyrosine deiodinase reaction scheme. Iodotyrosine deiodinase reaction 2.png
Iodotyrosine deiodinase reaction scheme.

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. [24] Low levels of iodide either through the diet or through iodide metabolism are associated with hypothyroidism, mental retardation, goiter, and developmental defects. [5] [8] [19] Because iodotyrosine deiodinase is responsible for scavenging iodide, mutations in this enzyme result in iodide deficiency. [25]

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. [26] 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. [27] However, mutations of iodotyrosine deiodinase are often not detected until after developmental damage has already occurred. [19] Furthermore, these mutations may not be specifically detected using standard thyroid function tests. [19] To combat this issue, a sensitive assay has recently been created that measures the amounts of mono- and diiodotyrosine in the urine. [26]

See also

Related Research Articles

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus (pl.: isthmi). The thyroid gland is a butterfly-shaped gland located in the neck below the Adam's apple. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid. The thyroid gland secretes three hormones: the two thyroid hormones – triiodothyronine (T3) and thyroxine (T4) – and a peptide hormone, calcitonin. The thyroid hormones influence the metabolic rate and protein synthesis and growth and development in children. Calcitonin plays a role in calcium homeostasis. Secretion of the two thyroid hormones is regulated by thyroid-stimulating hormone (TSH), which is secreted from the anterior pituitary gland. TSH is regulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

<span class="mw-page-title-main">Hypothyroidism</span> Endocrine disease

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

<span class="mw-page-title-main">Iodothyronine deiodinase</span> Class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

<span class="mw-page-title-main">Triiodothyronine</span> Chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

<span class="mw-page-title-main">Propylthiouracil</span> Medication used to treat hyperthyroidism

Propylthiouracil (PTU) is a medication used to treat hyperthyroidism. This includes hyperthyroidism due to Graves' disease and toxic multinodular goiter. In a thyrotoxic crisis it is generally more effective than methimazole. Otherwise it is typically only used when methimazole, surgery, and radioactive iodine is not possible. It is taken by mouth.

<span class="mw-page-title-main">Thyroid peroxidase</span> Enzyme expressed mainly in the thyroid gland

Thyroid peroxidase, also called thyroperoxidase (TPO), thyroid specific peroxidase or iodide peroxidase, is an enzyme expressed mainly in the thyroid where it is secreted into colloid. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3), the thyroid hormones. In humans, thyroperoxidase is encoded by the TPO gene.

<span class="mw-page-title-main">Thyroxine 5-deiodinase</span> Protein-coding gene in the species Homo sapiens

Thyroxine 5-deiodinase also known as type III iodothyronine deiodinase (EC number 1.21.99.3) is an enzyme that in humans is encoded by the DIO3 gene. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Thyrotropin receptor</span> Mammalian protein found in Homo sapiens

The thyrotropin receptor is a receptor that responds to thyroid-stimulating hormone and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

<span class="mw-page-title-main">Reverse triiodothyronine</span> Chemical compound

Reverse triiodothyronine (3,3′,5′-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3′ triiodothyronine, T3).

An antithyroid agent is a hormone inhibitor acting upon thyroid hormones.

<span class="mw-page-title-main">Sodium/iodide cotransporter</span> Mammalian protein found in Homo sapiens

The sodium/iodide cotransporter, also known as the sodium/iodide symporter (NIS), is a protein that in humans is encoded by the SLC5A5 gene. It is a transmembrane glycoprotein with a molecular weight of 87 kDa and 13 transmembrane domains, which transports two sodium cations (Na+) for each iodide anion (I−) into the cell. NIS mediated uptake of iodide into follicular cells of the thyroid gland is the first step in the synthesis of thyroid hormone.

<span class="mw-page-title-main">DIO2</span> Protein-coding gene in the species Homo sapiens

Type II iodothyronine deiodinase is an enzyme that in humans is encoded by the DIO2 gene.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

Organoiodine chemistry is the study of the synthesis and properties of organoiodine compounds, or organoiodides, organic compounds that contain one or more carbon–iodine bonds. They occur widely in organic chemistry, but are relatively rare in nature. The thyroxine hormones are organoiodine compounds that are required for health and the reason for government-mandated iodization of salt.

Deiodinase (monodeiodinase) is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

<span class="mw-page-title-main">3-Iodotyrosine</span> Chemical compound

3-Iodotyrosine is an intermediate in the synthesis of thyroid hormones which is derived from iodination of tyrosine at the meta-position of the benzene ring. One unit can combine with diiodotyrosine to form triiodothyronine, as occurs in the colloid of the thyroid follicle. Two units can combine to form 3,3'-diiodothyronine.

<span class="mw-page-title-main">Iodine in biology</span> Use of Iodine by organisms

Iodine is an essential trace element in biological systems. It has the distinction of being the heaviest element commonly needed by living organisms as well as the second-heaviest known to be used by any form of life. It is a component of biochemical pathways in organisms from all biological kingdoms, suggesting its fundamental significance throughout the evolutionary history of life.

<span class="mw-page-title-main">Plummer effect</span>

The Plummer effect is one of several physiological feedforward mechanisms taking place in follicular cells of the healthy thyroid gland and preventing the development of thyrotoxicosis in situations of extremely high supply with iodine.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000009765 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000019762 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Moreno 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. PMID   20298747. S2CID   24169254.
  6. ↑ Green WL (August 1968). "Inhibition of thyroidal iodotyrosine deiodination by tyrosine analogues". Endocrinology. 83 (2): 336–47. doi:10.1210/endo-83-2-336. PMID   5668272.
  7. ↑ 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. PMID   13345866.
  8. 1 2 3 4 5 6 7 8 9 Rokita SE, Adler JM, McTamney PM, Watson JA (September 2010). "Efficient use and recycling of the micronutrient iodide in mammals". Biochimie. 92 (9): 1227–35. doi:10.1016/j.biochi.2010.02.013. PMC   2888766 . PMID   20167242.
  9. ↑ Häggblom M, Bossert I (2003). Dehalogenation: Microbial Processes and Environmental Applications. Boston: Kluwer Academic Publishers. p. 520. ISBN   978-1-4757-7807-6.
  10. ↑ 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 . PMID   12847093.
  11. 1 2 Watson JA, McTamney PM, Adler JM, Rokita SE (March 2008). "Flavoprotein iodotyrosine deiodinase functions without cysteine residues". ChemBioChem. 9 (4): 504–6. doi:10.1002/cbic.200700562. PMID   18228228. S2CID   39353323.
  12. 1 2 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 (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 . PMID   15289438. S2CID   46192142.
  13. 1 2 3 Friedman 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 . PMID   16316988.
  14. 1 2 3 4 5 6 7 Thomas SR, McTamney PM, Adler JM, Laronde-Leblanc N, Rokita SE (July 2009). "Crystal structure of iodotyrosine deiodinase, a novel flavoprotein responsible for iodide salvage in thyroid glands". The Journal of Biological Chemistry. 284 (29): 19659–67. doi: 10.1074/jbc.M109.013458 . PMC   2740591 . PMID   19436071.
  15. ↑ Rosenberg IN, Goswami A (1 January 1984). "Iodotyrosine deiodinase from bovine thyroid". Posttranslational Modifications Part B. Methods in Enzymology. Vol. 107. pp. 488–500. doi:10.1016/0076-6879(84)07033-6. ISBN   9780121820077. PMID   6503724.
  16. ↑ "RCSB PDB - Search Results". www.rcsb.org. RCSB Protein Data Banck. Retrieved 1 March 2016.
  17. 1 2 "Entrez Gene: IYD Iodotyrosine deiodinase". Entrez Gene. United States National Library of Medicine.
  18. ↑ 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. doi: 10.1016/S0021-9258(19)86318-4 . PMID   500717.
  19. 1 2 3 4 Moreno 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 . PMID   18434651.
  20. ↑ 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. PMID   14558921.
  21. ↑ 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 (7): 983–1003. doi:10.1210/jcem-20-7-983. PMID   13810029.
  22. ↑ 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. doi: 10.1016/S0021-9258(19)86319-6 . PMID   500718.
  23. ↑ Mansoorabadi SO, Thibodeaux CJ, Liu HW (August 2007). "The diverse roles of flavin coenzymes--nature's most versatile thespians". The Journal of Organic Chemistry. 72 (17): 6329–42. doi:10.1021/jo0703092. PMC   2519020 . PMID   17580897.
  24. ↑ Eastman CJ, Zimmermann M (1 January 2000). 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. PMID   25905411.
  25. ↑ Lever EG, Medeiros-Neto GA, DeGroot LJ (1983). "Inherited disorders of thyroid metabolism". Endocrine Reviews. 4 (3): 213–39. doi:10.1210/edrv-4-3-213. PMID   6354701.
  26. 1 2 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 . PMID   18765512.
  27. ↑ 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. PMID   6118534. S2CID   44605217.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.