Thyroid peroxidase

Function

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.

Catalyzed reaction

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|x30px|L-Tyrosin]] + I− + H2O2 + H+ = [thyroglobulin]-3-iodo-L-tyrosine [[File:3-Iod-L-Tyrosin.svg|x30px|3-Iod-L-Tyrosin]] + 2 H2O
3. Generation of 3,5-iodo-tyrosine, [thyroglobulin]-3-iodo-L-tyrosine [[File:3-Iod-L-Tyrosin.svg|x30px|3-Iod-L-Tyrosin]] + I− + H2O2 + H+ = [thyroglobulin]-3,5-diiodo-L-tyrosine [[File:3,5-Diiod-L-Tyrosin.svg|x30px|3,5-Diiod-L-Tyrosin]] + 2 H2O
4. Coupling to produce T4, 2 [thyroglobulin]-3,5-diiodo-L-tyrosine [[File:3,5-Diiod-L-Tyrosin.svg|x30px|3,5-Diiod-L-Tyrosin]] + H2O2 = [thyroglobulin]-L-thyroxine [[File:Thyroxine2.svg|x30px]] + [thyroglobulin]-dehydroalanine [[File:Dehydroalanin.svg|x30px]] + 2 H2O
5. Coupling to produce T3, [thyroglobulin]-3-iodo-L-tyrosine [[File:3-Iod-L-Tyrosin.svg|x30px|3-Iod-L-Tyrosin]] + [thyroglobulin]-3,5-diiodo-L-tyrosine [[File:3,5-Diiod-L-Tyrosin.svg|x30px|3,5-Diiod-L-Tyrosin]] + H2O2 = [thyroglobulin]-3,3',5-triiodo-L-thyronine [[File:Liothyronine2DCSD.svg|x30px]] + [thyroglobulin]-dehydroalanine [[File:Dehydroalanin.svg|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.

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. T2 and T1 are also known to occur naturally.

Stimulation and inhibition

TPO is stimulated by TSH, which upregulates gene expression.

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

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.

Diagnostic use

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

Biotechnology

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

References

References

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12. (May 1996). "Immunohistochemical loss of thyroid peroxidase in papillary thyroid carcinoma: strong suppression of peroxidase gene expression". The Journal of Pathology.
13. (18 March 2020). "Tyrosinase-Mediated Oxidative Coupling of Tyrosine Tags on Peptides and Proteins". Journal of the American Chemical Society.