Thyroid peroxidase

iodide peroxidase
iodide peroxidase monomer, Zobellia galactanivorans
Identifiers
EC no.1.11.1.8
CAS no.9031-28-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
thyroid peroxidase
Identifiers
SymbolTPO
NCBI gene7173
HGNC12015
OMIM606765
RefSeqNM_175722
UniProtP07202
Other data
EC number1.11.1.8
LocusChr. 2 pter-p24
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StructuresSwiss-model
DomainsInterPro

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]

Function

Thyroid hormone synthesis, with thyroid peroxidase performing the oxidation and conjugation steps seen at center-left in the image.[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.[4]

Catalyzed reaction

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

  • 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.[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]

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. ^ a b c 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.