The importance of thyroglobulin structure for thyroid hormone biosynthesis**We shared with our friend and colleague, the late Gaetano Salvatore, a long–standing interest in thyroglobulin structure, as well as a broader interest in the optimal production of thyroid hormone and its dependence on adequate iodine supply. Over the years, we frequently discussed progress in this field with him and his many co–workers. We now welcome the opportunity to review some of our investigative work in one of his favorite

Dunn, John T.; Dunn, Ann D.

doi:10.1016/s0300-9084(99)80102-3

Cited by 49 publications

(16 citation statements)

References 40 publications

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“…[37] In mature Tg,only four tyrosine residues at positions 5, 2553, 2746, and 1290 are associated with the hormone synthesis. [38] Accordingly,these four sites are designated as A, B, C, and D, with A being the major hormonogenic site.I nm ost species,s ites A and Ba ccount for 40 %a nd 25 %, respectively,o ft he TH production. In contrast, site Cisprobably associated with the production of T3 in some species,a nd TSH appears to favor hormonogenesis at site Di ng uinea pigs and rabbits.…”

Section: Thyroglobulin and T4 Biosynthesismentioning

confidence: 99%

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

et al. 2016

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Thyroid hormones (THs) are secreted by the thyroid gland. They control lipid, carbohydrate, and protein metabolism, heart rate, neural development, as well as cardiovascular, renal, and brain functions. The thyroid gland mainly produces l-thyroxine (T4) as a prohormone, and 5'-deiodination of T4 by iodothyronine deiodinases generates the nuclear receptor binding hormone T3. In this Review, we discuss the basic aspects of the chemistry and biology as well as recent advances in the biosynthesis of THs in the thyroid gland, plasma transport, and internalization of THs in their target organs, in addition to the deiodination and various other enzyme-mediated metabolic pathways of THs. We also discuss thyroid hormone receptors and their mechanism of action to regulate gene expression, as well as various thyroid-related disorders and the available treatments.

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Section: Thyroglobulin and T4 Biosynthesismentioning

confidence: 99%

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

et al. 2016

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“…T4 is formed by the conjugation of two residues of diiodotyrosine followed by cleavage. T3 is formed in a similar manner, but through the conjugation of diiodotyrosine with monoiodotyrosine [6,7]. T3 is the functional form; it is generated principally by T4 deiodinases in the peripheral organs, with only 13% being formed in the thyroid gland [8].…”

Section: Introductionmentioning

confidence: 99%

Phylogenetic analysis of the human thyroglobulin regions

et al. 2012

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Thyroglobulin is a large protein present in all vertebrates. It is synthesized in the thyrocytes and exported to lumen of the thyroid follicle, where its tyrosine residues are iodinated . The iodinated thyroglobulin is reintegrated into the cell and processed (cleaved to free its two extremities) for thyroid hormone synthesis. Thyroglobulin sequence analysis has identified four regions of the molecule: Tg1, Tg2, Tg3 and ChEL. Structural abnormalities and mutations result in different pathological consequences, depending on the thyroglobulin region affected. We carried out a bioinformatic analysis of thyroglobulin, determining the origin and the function of each region. Our results suggest that the Tg1 region acts as a binding protein on the apical membrane, the Tg2 region is involved in protein adhesion and the Tg3 region is involved in determining the three-dimensional structure of the protein. The ChEL domain is involved in thyroglobulin transport, dimerization and adhesion. The presence of repetitive domains in the Tg1, Tg2 and Tg3 regions suggests that these domains may have arisen through duplication.

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“…Palumbo et al (37) noted that of the 140 tyrosines in the Tg dimer in rats, only 25-30 are normally iodinated and a much smaller number undergo coupling to form thyroid hormones (T3 and T4). Dunn et al (38,39) mentioned the presence of four essential hormonogenic sites in rabbit Tg. Those sites, designated A, B, C, and D, were found either experimentally or by homology when the cDNA sequences were established (16,40,41).…”

Section: Discussionmentioning

confidence: 99%

“…Dunn et al (39) proposed a classification of iodinated tyrosyl groups into three consensus families: ((D/E)Y), ((S/ T)YS)), and (EXY) motives. (i) The ((D/E)Y) di-amino acid consensus was associated with T4 at sites A, B, and D. This is also the case in mouse Tg as supported by our results.…”

Section: Discussionmentioning

confidence: 99%

Revisiting Iodination Sites in Thyroglobulin with an Organ-oriented Shotgun Strategy

Dedieu

Gaillard

Pourcher³

et al. 2011

Journal of Biological Chemistry

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Thyroglobulin (Tg) is secreted by thyroid epithelial cells. It is essential for thyroid hormonogenesis and iodine storage. Although studied for many years, only indirect and partial surveys of its post-translational modifications were reported. Here, we present a direct proteomic approach, used to study the degree of iodination of mouse Tg without any preliminary purification. A comprehensive coverage of Tg was obtained using a combination of different proteases, MS/MS fragmentation procedures with inclusion lists and a hybrid mass highresolution LTQ-Orbitrap XL mass spectrometer. Although only 16 iodinated sites are currently known for human Tg, we uncovered 37 iodinated tyrosine residues, most of them being mono-or diiodinated. We report the specific isotopic pattern of thyroxine modification, not recognized as a normal peptide pattern. Four hormonogenic sites were detected. Two donor sites were identified through the detection of a pyruvic acid residue in place of the initial tyrosine. Evidence for polypeptide cleavages sites due to the action of cathepsins and dipeptidyl proteases in the thyroid were also detected. This work shows that semi-quantitation of Tg iodination states is feasible for human biopsies and should be of significant medical interest for further characterization of human thyroid pathologies.Thyroglobulin (Tg) 3 is one of the most abundant proteins produced by the thyroid gland and comprises two identical subunits of ϳ330 kDa. This prohormonal glycoprotein is secreted by thyroid epithelial cells. It is stored in the lumen of thyroid follicles in a highly condensed and covalently crosslinked form with numerous disulfide bridges. There, Tg is used as a scaffold for thyroid hormonogenesis and as an iodine reservoir. Many post-translational modifications are known to occur on this protein such as glycosylation, sulfation, and iodination (1). A signal peptide is processed during its export to the lumen. The most specific Tg post-translational modification is certainly its iodination and 3,5,3Ј-triiodothyronine (T3) and thyroxine (T4) thyroid hormone synthesis. Indeed, through the combined action of NADPH oxidase and thyroperoxidase on the outer surface of the thyrocyte apical membrane, iodide ions that are also transported to the follicular lumen are covalently linked to some Tg tyrosyl residues to form mono-or diiodotyrosines (MIT or DIT, respectively). Coupling of two of these DIT residues then leads to the formation of T4 at an acceptor site, whereas coupling one MIT and one DIT moiety essentially forms T3 (2). In this reaction, the release of an iodotyrosyl moiety at the donor site leaves an "empty" side chain and the fate of this unusual residue is controversial. Some authors claim that a dehydroalanine is left instead of the tyrosine, whereas others observed pyruvic acid associated with cleavage of the polypeptide chain (3-7). Finally, the protein is proteolytically processed in the lumen, followed by endocytosis in lysosomes, to release the hormones. The principal proteases involved inclu...

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Cited by 49 publications

References 40 publications

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones

Phylogenetic analysis of the human thyroglobulin regions

Revisiting Iodination Sites in Thyroglobulin with an Organ-oriented Shotgun Strategy

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