Thyroid peroxidase

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iodide peroxidase
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iodide peroxidase monomer, Zobellia galactanivorans
Identifiers
EC no. 1.11.1.8
CAS no. 9031-28-1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
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PMC articles
PubMed articles
NCBI proteins
thyroid peroxidase
Identifiers
SymbolTPO
NCBI gene 7173
HGNC 12015
OMIM 606765
RefSeq NM_175722
UniProt P07202
Other data
EC number 1.11.1.8
Locus Chr. 2 pter-p24
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Structures Swiss-model
Domains InterPro

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. [1] In humans, thyroperoxidase is encoded by the TPO gene. [2]

Contents

Function

Thyroid hormone synthesis, with thyroid peroxidase performing the oxidation and conjugation steps seen at center-left in the image. Thyroid hormone synthesis.png
Thyroid hormone synthesis, with thyroid peroxidase performing the oxidation and conjugation steps seen at center-left in the image.

Inorganic iodine enters the body primarily as iodide, I−. After entering the thyroid follicle (or thyroid follicular cell) via a Na+/I− symporter (NIS) on the basolateral side, iodide is shuttled across the apical membrane into the colloid via pendrin after which thyroid peroxidase oxidizes iodide to atomic iodine (I) or iodinium (I+). The chemical reactions catalyzed by thyroid peroxidase occur on the outer apical membrane surface and are mediated by hydrogen peroxide.

The "organification of iodine", the incorporation of iodine into thyroglobulin for the production of thyroid hormone, is nonspecific; that is, there is no TPO-bound intermediate, but iodination occurs via reactive iodine species released from TPO. Ascidians (tunicates or sea squirts) and amphioxus, which are close invertebrate relatives of vertebrates, have a primitive homolog of the thyroid known as the endostyle. They do not have a thyroglobulin gene that produce a protein intended specifically for making thyroxine, but do produce thyroxine. Presumably they simply rely on the nonspecific action. [4]

Catalyzed reaction

A higher-level view of the conjugation process (the first and the second arrows). Thyroxine biosynthesis.svg
A higher-level view of the conjugation process (the first and the second arrows).

The reactions registered with Enzyme Commission no. 1.11.1.8 are:

  1. Conversion of iodide to diiodine, 2 I− + H2O2 + 2 H+ = I2 + 2 H2O
  2. Generation of 3-iodo-tyrosine, [thyroglobulin]-L-tyrosine L-Tyrosin phys.svg + I− + H2O2 + H+ = [thyroglobulin]-3-iodo-L-tyrosine 3-Iod-L-Tyrosin.svg + 2 H2O
  3. Generation of 3,5-iodo-tyrosine, [thyroglobulin]-3-iodo-L-tyrosine 3-Iod-L-Tyrosin.svg + I− + H2O2 + H+ = [thyroglobulin]-3,5-diiodo-L-tyrosine 3,5-Diiod-L-Tyrosin.svg + 2 H2O
  4. Coupling to produce T4, 2 [thyroglobulin]-3,5-diiodo-L-tyrosine 3,5-Diiod-L-Tyrosin.svg + H2O2 = [thyroglobulin]-L-thyroxine Thyroxine2.svg + [thyroglobulin]-dehydroalanine Dehydroalanin.svg + 2 H2O
  5. Coupling to produce T3, [thyroglobulin]-3-iodo-L-tyrosine 3-Iod-L-Tyrosin.svg + [thyroglobulin]-3,5-diiodo-L-tyrosine 3,5-Diiod-L-Tyrosin.svg + H2O2 = [thyroglobulin]-3,3',5-triiodo-L-thyronine Liothyronine2DCSD.svg + [thyroglobulin]-dehydroalanine Dehydroalanin.svg + 2 H2O

However, in light of the non-specific organification by TPO, it would be useful to distinguish which actions are the "true" functions of TPO. Under the model of Kessler et al. (2008), the real functions of TPO are: [4]

Both actions are mediated by the oxidized form of TPO, TPO-O, produced by reaction of TPO with hydrogen peroxide. [4]

Side reactions

T3 is produced when a MIT free radical couples to a DIT residue on a protein. Coupling of DIT to MIT in the opposite order yields a substance, r-T3, which is biologically inactive. [5] [6] T2 and T1 are also known to occur naturally. [7]

Stimulation and inhibition

TPO is stimulated by TSH, which upregulates gene expression.

TPO is inhibited by the thioamide drugs, such as propylthiouracil and methimazole. [8] In laboratory rats with insufficient iodine intake, genistein has demonstrated inhibition of TPO. [9]

Clinical significance

Thyroid peroxidase is a frequent epitope of autoantibodies in autoimmune thyroid disease, with such antibodies being called anti-thyroid peroxidase antibodies (anti-TPO antibodies). This is most commonly associated with Hashimoto's thyroiditis. Thus, an antibody titer can be used to assess disease activity in patients that have developed such antibodies. [10] [11]

Diagnostic use

In diagnostic immunohistochemistry, the expression of thyroid peroxidase (TPO) is lost in papillary thyroid carcinoma. [12]

Biotechnology

TPO's ability to non-selectively couple tyrosine residues together has been used to modify protein tags. [13]

Related Research Articles

<span class="mw-page-title-main">Thyroid</span> Endocrine gland in the neck

The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus. 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.

<span class="mw-page-title-main">Hypothyroidism</span> Insufficient production of thyroid hormones by the thyroid gland

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, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. 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">Thyroxine</span> Chemical compound

Thyroxine, also known as T4, is a hormone produced by the thyroid gland. It is the primary form of thyroid hormone found in the blood and acts as a prohormone of the more active thyroid hormone, triiodothyronine (T3). Thyroxine and its active metabolites are essential for regulating metabolic rate, supporting heart and muscle function, promoting brain development, and maintaining bone health.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<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">Thyroglobulin</span> Protein produced and used by the thyroid

Thyroglobulin (Tg) is a 660 kDa, dimeric glycoprotein produced by the follicular cells of the thyroid and used entirely within the thyroid gland. Tg is secreted and accumulated at hundreds of grams per litre in the extracellular compartment of the thyroid follicles, accounting for approximately half of the protein content of the thyroid gland. Human TG (hTG) is a homodimer of subunits each containing 2768 amino acids as synthesized.

<span class="mw-page-title-main">Thyroid follicular cell</span> Hormone-producing cell in the thyroid gland

Thyroid follicular cells (also called thyroid epithelial cells or thyrocytes) are the major cell type in the thyroid gland, and are responsible for the production and secretion of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). They form the single layer of cuboidal epithelium that makes up the outer structure of the almost spherical thyroid follicle.

<span class="mw-page-title-main">Hashimoto's thyroiditis</span> Autoimmune disease

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, Hashimoto's disease and autoimmune thyroiditis, is an autoimmune disease in which the thyroid gland is gradually destroyed.

<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 disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

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

<span class="mw-page-title-main">Animal heme-dependent peroxidases</span> Protein family

Animal heme-dependent peroxidases is a family of peroxidases. Peroxidases are found in bacteria, fungi, plants and animals. On the basis of sequence similarity, a number of animal heme peroxidases can be categorized as members of a superfamily: myeloperoxidase (MPO); eosinophil peroxidase (EPO); lactoperoxidase (LPO); thyroid peroxidase (TPO); prostaglandin H synthase (PGHS); and peroxidasin.

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

Thyroid hormones are two hormones produced and released by the thyroid gland, 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.

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

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

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

<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.

Organification is a biochemical process that takes place in the thyroid gland. It is the incorporation of iodine into thyroglobulin for the production of thyroid hormone, a step done after the oxidation of iodide by the enzyme thyroid peroxidase (TPO) Since iodine is an inorganic compound, and is being attached to thyroglobulin, a protein, the process is termed as "organification of iodine".

Antithyroid autoantibodies (or simply antithyroid antibodies) are autoantibodies targeted against one or more components on the thyroid. The most clinically relevant anti-thyroid autoantibodies are anti-thyroid peroxidase antibodies (anti-TPO antibodies, TPOAb), thyrotropin receptor antibodies (TRAb) and thyroglobulin antibodies (TgAb). TRAb's are subdivided into activating, blocking and neutral antibodies, depending on their effect on the TSH receptor. Anti-sodium/iodide (Anti–Na+/I−) symporter antibodies are a more recent discovery and their clinical relevance is still unknown. Graves' disease and Hashimoto's thyroiditis are commonly associated with the presence of anti-thyroid autoantibodies. Although there is overlap, anti-TPO antibodies are most commonly associated with Hashimoto's thyroiditis and activating TRAb's are most commonly associated with Graves' disease. Thyroid microsomal antibodies were a group of anti-thyroid antibodies; they were renamed after the identification of their target antigen (TPO).

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

Eosinophil peroxidase is an enzyme found within the eosinophil granulocytes, innate immune cells of humans and mammals. This oxidoreductase protein is encoded by the gene EPX, expressed within these myeloid cells. EPO shares many similarities with its orthologous peroxidases, myeloperoxidase (MPO), lactoperoxidase (LPO), and thyroid peroxidase (TPO). The protein is concentrated in secretory granules within eosinophils. Eosinophil peroxidase is a heme peroxidase, its activities including the oxidation of halide ions to bacteriocidal reactive oxygen species, the cationic disruption of bacterial cell walls, and the post-translational modification of protein amino acid residues.

References

  1. ↑ Ruf J, Carayon P (Jan 2006). "Structural and functional aspects of thyroid peroxidase". Archives of Biochemistry and Biophysics. 445 (2): 269–77. doi: 10.1016/j.abb.2005.06.023 . PMID   16098474.
  2. ↑ Kimura S, Kotani T, McBride OW, Umeki K, Hirai K, Nakayama T, Ohtaki S (Aug 1987). "Human thyroid peroxidase: complete cDNA and protein sequence, chromosome mapping, and identification of two alternately spliced mRNAs". Proceedings of the National Academy of Sciences of the United States of America. 84 (16): 5555–9. Bibcode:1987PNAS...84.5555K. doi: 10.1073/pnas.84.16.5555 . PMC   298901 . PMID   3475693.
  3. ↑ Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN   1-4160-2328-3.
  4. 1 2 3 Kessler J, Obinger C, Eales G (Jul 2008). "Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis". Thyroid. 18 (7): 769–74. doi:10.1089/thy.2007.0310. PMID   18631006.
  5. ↑ Rousset B, Dupuy C, Miot F, Dumont J (2000). "Chapter 2 Thyroid Hormone Synthesis And Secretion". In Feingold KR, Anawalt B, Boyce A, Chrousos G (eds.). Endotext. South Dartmouth (MA): MDText.com, Inc. PMID   25905405 . Retrieved 2022-11-23.
  6. ↑ Li D, Zhang Y, Fan Z, Chen J, Yu J (November 2015). "Coupling of chromophores with exactly opposite luminescence behaviours in mesostructured organosilicas for high-efficiency multicolour emission". Chemical Science. 6 (11): 6097–6101. doi:10.1039/c5sc02044a. PMC   6054107 . PMID   30090223.
  7. ↑ Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L (July 2006). "Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials". The Journal of Clinical Endocrinology and Metabolism. 91 (7): 2592–2599. doi: 10.1210/jc.2006-0448 . PMID   16670166.
  8. ↑ Nagasaka A, Hidaka H (Jul 1976). "Effect of antithyroid agents 6-propyl-2-thiouracil and 1-methyl-2-mercaptoimidazole on human thyroid iodine peroxidase". The Journal of Clinical Endocrinology and Metabolism. 43 (1): 152–8. doi:10.1210/jcem-43-1-152. PMID   947933.
  9. ↑ Doerge DR, Sheehan DM (Jun 2002). "Goitrogenic and estrogenic activity of soy isoflavones". Environmental Health Perspectives. 110 (Suppl 3): 349–53. doi:10.1289/ehp.02110s3349. PMC   1241182 . PMID   12060828.
  10. ↑ McLachlan SM, Rapoport B (2000). "Autoimmune response to the thyroid in humans: thyroid peroxidase--the common autoantigenic denominator". International Reviews of Immunology. 19 (6): 587–618. doi:10.3109/08830180009088514. PMID   11129117. S2CID   11431166.
  11. ↑ Chardès T, Chapal N, Bresson D, Bès C, Giudicelli V, Lefranc MP, Péraldi-Roux S (Jun 2002). "The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases" (PDF). Immunogenetics. 54 (3): 141–57. doi:10.1007/s00251-002-0453-9. PMID   12073143. S2CID   2701974.
  12. ↑ Tanaka T, Umeki K, Yamamoto I, Sugiyama S, Noguchi S, Ohtaki S (May 1996). "Immunohistochemical loss of thyroid peroxidase in papillary thyroid carcinoma: strong suppression of peroxidase gene expression". The Journal of Pathology. 179 (1): 89–94. doi:10.1002/(SICI)1096-9896(199605)179:1<89::AID-PATH546>3.0.CO;2-R. PMID   8691351. S2CID   26045198.
  13. ↑ Marmelstein AM, Lobba MJ, Mogilevsky CS, Maza JC, Brauer DD, Francis MB (18 March 2020). "Tyrosinase-Mediated Oxidative Coupling of Tyrosine Tags on Peptides and Proteins". Journal of the American Chemical Society. 142 (11): 5078–5086. doi:10.1021/jacs.9b12002.
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