Thyroid peroxidase

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iodide peroxidase
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iodide peroxidase monomer, Zobellia galactanivorans
Identifiers
EC number 1.11.1.8
CAS number 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
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

Thyroid peroxidase, also called thyroperoxidase (TPO) 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

Catalyzed reaction

L-Tyrosin phys.svg + I + H+ + H2O2 3-Iod-L-Tyrosin.svg + 2 H2O

Iodide is oxidized to iodine radical which immediately reacts with tyrosine.

3-Iod-L-Tyrosin.svg + I + H+ + H2O2 3,5-Diiod-L-Tyrosin.svg + 2 H2O

The second iodine atom is added in similar manner to the reaction intermediate 3-iodotyrosine.

Function

Thyroid hormone synthesis, with thyroid peroxidase performing the oxidation step seen at center-left in the image. Thyroid hormone synthesis.png
Thyroid hormone synthesis, with thyroid peroxidase performing the oxidation step 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 "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. [4] The chemical reactions catalyzed by thyroid peroxidase occur on the outer apical membrane surface and are mediated by hydrogen peroxide.

Stimulation and inhibition

TPO is stimulated by TSH, which upregulates gene expression.

TPO is inhibited by the thioamide drugs, such as propylthiouracil and methimazole. [5] In laboratory rats with insufficient iodine intake, genistein has demonstrated inhibition of TPO. [6]

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. [7] [8]

Diagnostic use

In diagnostic immunohistochemistry, the expression of thyroid peroxidase (TPO) is lost in papillary thyroid carcinoma. [9]

Related Research Articles

Thyroid Endocrine gland in the neck; secretes hormones that influence metabolism

The thyroid, or thyroid gland, is an endocrine gland in the neck consisting of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thyroid is located at the front of 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 in children, growth and development. 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.

Hypothyroidism Endocrine disease

Hypothyroidism, also called underactive thyroid or low thyroid, is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. 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 goiter. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

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.

Triiodothyronine

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.

Thyroglobulin

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.

Thyroid follicular cell

Thyroid follicular cells 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.

Hashimotos thyroiditis Autoimmune disease

Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis and Hashimoto's disease, is an autoimmune disease in which the thyroid gland is gradually destroyed. Early on, symptoms may not be noticed. Over time, the thyroid may enlarge, forming a painless goiter. Some people eventually develop hypothyroidism with accompanying weight gain, fatigue, constipation, depression, hair loss, and general pains. After many years the thyroid typically shrinks in size. Potential complications include thyroid lymphoma.

Propylthiouracil

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.

The Wolff–Chaikoff effect is a presumed reduction in thyroid hormone levels caused by ingestion of a large amount of iodine.

Thyroid disease

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 antagonist acting upon thyroid hormones.

Sodium/iodide cotransporter

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.

Animal heme-dependent peroxidases

Animal heme-dependent peroxidases is a family of peroxidases.

Thyroid hormones

Thyroid hormones are two 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. 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. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.

Autoimmune thyroiditis, is a chronic disease in which the body interprets the thyroid glands and its hormone products T3, T4 and TSH as threats, therefore producing special antibodies that target the thyroid's cells, thereby destroying it.

Iodotyrosine deiodinase

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 is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

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.

Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards.This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.

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).

References

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  3. Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN   1-4160-2328-3.
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  5. Nagasaka A, Hidaka H (Jul 1976). "Effect of antithyroid agents 6-propyl-2-thiouracil and 1-mehtyl-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.
  6. 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.
  7. 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.
  8. 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". Immunogenetics. 54 (3): 141–57. doi:10.1007/s00251-002-0453-9. PMID   12073143. S2CID   2701974.
  9. 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.