Selenium, Iodine and Iron-Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism

Abstract

The adequate availability and metabolism of three essential trace elements, iodine, selenium and iron, provide the basic requirements for the function and action of the thyroid hormone system in humans, vertebrate animals and their evolutionary precursors. Selenocysteine-containing proteins convey both cellular protection along with H₂O₂-dependent biosynthesis and the deiodinase-mediated (in-)activation of thyroid hormones, which is critical for their receptor-mediated mechanism of cellular action. Disbalances between the thyroidal content of these elements challenge the negative feedback regulation of the hypothalamus-pituitary-thyroid periphery axis, causing or facilitating common diseases related to disturbed thyroid hormone status such as autoimmune thyroid disease and metabolic disorders. Iodide is accumulated by the sodium-iodide-symporter NIS, and oxidized and incorporated into thyroglobulin by the hemoprotein thyroperoxidase, which requires local H₂O₂ as cofactor. The latter is generated by the dual oxidase system organized as 'thyroxisome' at the surface of the apical membrane facing the colloidal lumen of the thyroid follicles. Various selenoproteins expressed in thyrocytes defend the follicular structure and function against life-long exposure to H₂O₂ and reactive oxygen species derived therefrom. The pituitary hormone thyrotropin (TSH) stimulates all processes required for thyroid hormone synthesis and secretion and regulates thyrocyte growth, differentiation and function. Worldwide deficiencies of nutritional iodine, selenium and iron supply and the resulting endemic diseases are preventable with educational, societal and political measures.

Keywords: SELENOP (selenoprotein P); biomarker; deiodinases; essential trace elements; gene variants; genetic predisposition; glutathione peroxidase; hemoprotein; iodine; iron; selenium; thioredoxin reductase; thyroid hormone system; thyroperoxidase.

Figure 1

Essential role of the three trace elements iodine, selenium and iron in thyroid hormone biosynthesis and activation. Abbreviations: NIS: Na⁺-Iodide-Symporter (iodide uptake); DUOX: dual oxidase (H₂O₂ generation); TPO: thyroperoxidase (hemoprotein); TG: thyroglobulin (synthesis and storage protein); GPX: glutathione peroxidase (antioxidant defense); DIO: deiodinase (TH in-/activation).

Figure 2

Structures of natural selenoamino acids, selenocysteine ((A), SeCys; CID 6326983) and selenomethionine ((C), SeMet; CID 105024), and their sulfur homologues, cysteine ((B), Cys; CID 5862) and methionine ((D), Met; CID 6137). Structures obtained from Pubchem National Center for Biotechnology Information (2023), https://pubchem.ncbi.nlm.nih.gov, accessed on 7 February 2023.

Figure 3

Nutritional sources of selenium and their utilization for biosynthesis of selenocysteine-containing proteins. Abbreviations: SeMet, selenomethionine; Sec, selenocysteine; GRX, glutathione reductase; TRX, thioredoxin; TXNRD, thioredoxin reductase; GSH, glutathione; MGL, methionine gamma-lyase; SCLY, selenocysteine lyase; SEPHS2, selenophosphate synthetase 2; SARS, seryl-tRNA synthetase; PSTK, phosphoseryl(Sep)-tRNA kinase; SEPSECS, Sep-tRNA:Sec-tRNA synthase; EEFSEC, Sec-specific eukaryotic elongation factor; SBP2, SECIS binding protein 2. Adapted from [69], Kang D, et al. (2020).

Figure 4

Expression of pGPx (Gpx3) mRNA detected in in situ hybridization (12 µm cryosection) of a human thyroid gland specimen, thyroidectomized for severe Hashimoto’s thyroiditis. Residual angiofollicular units stained for pGPx (brown); H&E stain of infiltrating lymphocytes; insert: negative control staining with an antisense pGPx probe. (Reproduced with permission from Figure 1C [6], Schmutzler C. et al. Biol. Chem. (2007), 388, 1053–1059; DOI:10.1515/BC.2007.122).