thyroid peroxidase

File:Thyroid hormone synthesis.png, with thyroid peroxidase performing the oxidation and conjugation steps seen at center-left in the image.{{cite book |author=Walter F., PhD. Boron |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |year=2003 |pages=1300 |isbn=1-4160-2328-3 }}]]

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.{{cite journal | vauthors = Kessler J, Obinger C, Eales G | title = Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis | journal = Thyroid | volume = 18 | issue = 7 | pages = 769–74 | date = Jul 2008 | pmid = 18631006 | doi = 10.1089/thy.2007.0310 }}

File:Thyroxine_biosynthesis.svg

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 File:L-Tyrosin phys.svg + I⁻ + H₂O₂ + H⁺ = [thyroglobulin]-3-iodo-L-tyrosine File:3-Iod-L-Tyrosin.svg + 2 H₂O
3. Generation of 3,5-iodo-tyrosine, [thyroglobulin]-3-iodo-L-tyrosine File:3-Iod-L-Tyrosin.svg + I⁻ + H₂O₂ + H⁺ = [thyroglobulin]-3,5-diiodo-L-tyrosine File:3,5-Diiod-L-Tyrosin.svg + 2 H₂O
4. Coupling to produce T₄, 2 [thyroglobulin]-3,5-diiodo-L-tyrosine File:3,5-Diiod-L-Tyrosin.svg + H₂O₂ = [thyroglobulin]-L-thyroxine x30px + [thyroglobulin]-dehydroalanine x30px + 2 H₂O
5. Coupling to produce T₃, [thyroglobulin]-3-iodo-L-tyrosine File:3-Iod-L-Tyrosin.svg + [thyroglobulin]-3,5-diiodo-L-tyrosine File:3,5-Diiod-L-Tyrosin.svg + H₂O₂ = [thyroglobulin]-3,3',5-triiodo-L-thyronine x30px + [thyroglobulin]-dehydroalanine x30px + 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:

• Conversion of iodide to diiodine, as in reaction (1) above. The I₂ produced would go on to react with OH⁻ to form HOI, which reacts with the tyrosyl residue on proteins such as thyroglobulin, explaining the reactions (2) and (3) above.
• Generation of free radicals from tyrosyl, 3-iodotyrosyl (MIT), and 3,5-diiodotyrosyl (DIT) residues or their free forms. These free radicals couple with iodized proteins (such as [thyroglobulin]-3,5-diiodo-L-tyrosine) to perform reactions (4) and (5).

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

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.{{cite book | vauthors = Rousset B, Dupuy C, Miot F, Dumont J | chapter = Chapter 2 Thyroid Hormone Synthesis And Secretion |date=2000 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK285550/ |title = Endotext | veditors = Feingold KR, Anawalt B, Boyce A, Chrousos G |place=South Dartmouth (MA) |publisher=MDText.com, Inc. |pmid=25905405 |access-date=2022-11-23 }}{{cite journal | vauthors = Li D, Zhang Y, Fan Z, Chen J, Yu J | title = Coupling of chromophores with exactly opposite luminescence behaviours in mesostructured organosilicas for high-efficiency multicolour emission | journal = Chemical Science | volume = 6 | issue = 11 | pages = 6097–6101 | date = November 2015 | pmid = 30090223 | pmc = 6054107 | doi = 10.1039/c5sc02044a }} T₂ and T₁ are also known to occur naturally.{{cite journal | vauthors = Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L | title = Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 7 | pages = 2592–2599 | date = July 2006 | pmid = 16670166 | doi = 10.1210/jc.2006-0448 | doi-access = free }}

TPO is stimulated by TSH, which upregulates gene expression.

TPO is inhibited by the thioamide drugs, such as propylthiouracil and methimazole.{{cite journal | vauthors = Nagasaka A, Hidaka H | title = Effect of antithyroid agents 6-propyl-2-thiouracil and 1-methyl-2-mercaptoimidazole on human thyroid iodine peroxidase | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 43 | issue = 1 | pages = 152–8 | date = Jul 1976 | pmid = 947933 | doi = 10.1210/jcem-43-1-152 }} In laboratory rats with insufficient iodine intake, genistein has demonstrated inhibition of TPO.{{cite journal | vauthors = Doerge DR, Sheehan DM | title = Goitrogenic and estrogenic activity of soy isoflavones | journal = Environmental Health Perspectives | volume = 110 | pages = 349–53 | date = Jun 2002 | issue = Suppl 3 | pmid = 12060828 | pmc = 1241182 | doi = 10.1289/ehp.02110s3349 }}

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.{{cite journal | vauthors = McLachlan SM, Rapoport B | title = Autoimmune response to the thyroid in humans: thyroid peroxidase--the common autoantigenic denominator | journal = International Reviews of Immunology | volume = 19 | issue = 6 | pages = 587–618 | year = 2000 | pmid = 11129117 | doi = 10.3109/08830180009088514 | s2cid = 11431166 }}{{cite journal | vauthors = Chardès T, Chapal N, Bresson D, Bès C, Giudicelli V, Lefranc MP, Péraldi-Roux S | title = The human anti-thyroid peroxidase autoantibody repertoire in Graves' and Hashimoto's autoimmune thyroid diseases | journal = Immunogenetics | volume = 54 | issue = 3 | pages = 141–57 | date = Jun 2002 | pmid = 12073143 | doi = 10.1007/s00251-002-0453-9 | s2cid = 2701974 | url = https://hal.science/hal-04335106/file/s00251-002-0453-9.pdf }}

In diagnostic immunohistochemistry, the expression of thyroid peroxidase (TPO) is lost in papillary thyroid carcinoma.{{cite journal | vauthors = Tanaka T, Umeki K, Yamamoto I, Sugiyama S, Noguchi S, Ohtaki S | title = Immunohistochemical loss of thyroid peroxidase in papillary thyroid carcinoma: strong suppression of peroxidase gene expression | journal = The Journal of Pathology | volume = 179 | issue = 1 | pages = 89–94 | date = May 1996 | pmid = 8691351 | doi = 10.1002/(SICI)1096-9896(199605)179:1<89::AID-PATH546>3.0.CO;2-R | s2cid = 26045198 }}

TPO's ability to non-selectively couple tyrosine residues together has been used to modify protein tags.{{cite journal |last1=Marmelstein |first1=Alan M. |last2=Lobba |first2=Marco J. |last3=Mogilevsky |first3=Casey S. |last4=Maza |first4=Johnathan C. |last5=Brauer |first5=Daniel D. |last6=Francis |first6=Matthew B. |title=Tyrosinase-Mediated Oxidative Coupling of Tyrosine Tags on Peptides and Proteins |journal=Journal of the American Chemical Society |date=18 March 2020 |volume=142 |issue=11 |pages=5078–5086 |doi=10.1021/jacs.9b12002|url=https://figshare.com/articles/journal_contribution/Tyrosinase-Mediated_Oxidative_Coupling_of_Tyrosine_Tags_on_Peptides_and_Proteins/11942070/1/files/21923946.pdf }}

{{Reflist|25em}}

• {{MeshName|Thyroid+Peroxidase}}

{{Thyroid hormone metabolism enzymes and transporters}}

{{Peroxidases}}

{{Enzymes}}

{{Thyroid hormone receptor modulators}}

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Category:EC 1.11.1

Category:Thyroid