The role of thyroglobulin in thyroid hormonogenesis
Open accessAbstract
In humans, the thyroid hormones T 3 and T 4 are synthesized in the thyroid gland in a process that crucially involves the iodoglycoprotein thyroglobulin. The overall structure of thyroglobulin is conserved in all vertebrates. Upon thyroglobulin delivery from thyrocytes to the follicular lumen of the thyroid gland via the secretory pathway, multiple tyrosine residues can become iodinated to form mono-iodotyrosine (MIT) and/or di-iodotyrosine (DIT); however, selective tyrosine residues lead to preferential formation of T 4 and T 3 at distinct sites. T 4 formation involves oxidative coupling between two DIT side chains, and de novo T 3 formation involves coupling between an MIT donor and a DIT acceptor. Thyroid hormone synthesis is stimulated by TSH activating its receptor (TSHR), which upregulates the activity of many thyroid gene products involved in hormonogenesis. Additionally, TSH regulates post-translational changes in thyroglobulin that selectively enhance its capacity for T 3 formation - this process is important in iodide deficiency and in Graves disease. 167 different mutations, many of which are newly discovered, are now known to exist in TG (encoding human thyroglobulin) that can lead to defective thyroid hormone synthesis, resulting in congenital hypothyroidism.
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TG is a protein dimer of 600 kDa with an unusually high number of ~60 disulfide bonds per monomer and 17 glycosylation sites, which confer remarkable stability and solubility to the protein.
“TG, a protein dimer of 600 kDa, has an unusually high number of ~ 60 disulfide bonds per monomer and 17 glycosylation sites, which confer remarkable stability and solubility to the protein1,2,9.”
From The structure of human thyroglobulin (2020) · cites this paper as [2]
A Results passage in the indexed copy describes TG as a homodimeric glycoprotein, supporting the dimer description. The passages do not give a 600 kDa mass, approximately 60 disulfide bonds per monomer, 17 glycosylation sites, or their proposed effect on stability and solubility. The indexed text also appears to contain a different article from the cited review, so those details cannot be verified against it. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTPO catalyzes the coupling of MIT and DIT in the same TG molecule to produce intramolecular T3 and T4.
“TPO then further catalyzes the coupling of MIT and DIT in the same TG molecule to produce intramolecular T3 and T4 (66).”
From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [66]
The indexed copy identifies the cited review in repository metadata, but the substantive text returned is from a different paper about TSH genetics (Results; no page given). Searches for TPO, MIT, DIT, and iodotyrosine coupling found no passage from the cited review addressing the claimed intramolecular formation of T3 and T4, so the attribution cannot be verified from this copy. (LLM, conf=0.73)
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Cites
Thyroid Hormone Regulation of Metabolism
Mullur, R., Liu, Y.-Y., & Brent, G. A. (2014) · Physiological Reviews · doi:10.1152/physrev.00030.2013 · Cited by 2,421 · see citing works
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Research works printed but not linked: 1
- [1]1. National Academies Press. Medicare Coverage of Routine Screening for Thyroid Dysfunction (National Academies Press, USA, 2003).
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Selenium, Iodine and Iron–Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism
Köhrle, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043393 · Cited by 163 · see citing works
The structure of human thyroglobulin
Coscia, F., Taler-Verčič, A., Chang, V. T., Sinn, L., O’Reilly, F. J., Izoré, T., Renko, M., Berger, I., Rappsilber, J., Turk, D., et al. (2020) · Nature · doi:10.1038/s41586-020-1995-4 · Cited by 147 · see citing works
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Self-citationIntrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion
Jing, L., & Zhang, Q. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.992883 · Cited by 61 · see citing works
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- Authors
- Citterio, C. E., Targovnik, H. M., & Arvan, P.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- University of Michigan (US)
- Corresponding author
- Arvan, Peter
- Venue
- Nature Reviews Endocrinology
- Published
- 2019-03-18
- Volume
- 15
- Issue
- 6
- Pages
- 323-338
- ISSN
- 1759-5029 (ISSN-L)
- 1759-5037
- OpenAlex
- W2921600269
- Cited by
- 216
- References
- 4
- Citations by year
- 2026: 22 · 2025: 28 · 2024: 32 · 2023: 33 · 2022: 34 · 2021: 35 · 2020: 24 · 2019: 8
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature Reviews Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Chapman University Digital Commons (Chapman University) (submittedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Chemical Analysis and Environmental Impact
- Keywords
- thyroglobulin, thyroid hormone synthesis, triiodothyronine, thyroxine, monoiodotyrosine, diiodotyrosine, TSH receptor, TSH regulation, iodide deficiency, Graves' disease, congenital hypothyroidism
- MeSH terms
- Animals, Graves Disease, Humans, Thyroglobulin, Thyroid Gland, Thyroid Hormones, Thyroxine, Triiodothyronine
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