1. Biochemistry of thyroid hormones
Vytášek 2009

2. 3,5,3´-triiodothyronine (T3)

3. Thyroxine (T4) 3,5,3´,5´-tetraiodothyronine

4. Biosynthesis of thyroid hormones and iodine metabolismus
Receptor for thyroid hormones and mechanisms of regulation of basal metabolismus by thyroid hormones
Regulation of production of thyroid hormones, TSH, receptor of TSH, TRH

5. Biosynthesis of thyroxine
The main synthetized thyroid hormone is thyroxine, but triiodothyronine is tentimes more potent
Precursor molecule for synthesis thyroid hormones is tyrosine derivative
Biosynthesis is perfomed on tyrosine residues bound in protein of thyroid gland – thyreoglobulin
The first step is transport of iodide into cells of folicle cells of thyroid gland
Active transport of iodide into the follicle cell is mediated iodide pump (the concentration outside is 25times lower than inside)

6. Biosynthesis of thyroxine
Thyreoglobulin, secreted into the lumen of thyroid gland, is iodinated in one or two positions of phenol ring of tyrosine residues
Iodination reagent is iodosyl cation I+, vhich is produced by two electron oxidation of iodide with hydrogen peroxide under catalysis of enzyme thyroid peroxidase
Electrophilic substitution of tyrosine ring by iodine in position 3 and 5 is pure chemical reaction

7. Precursor molecule (Tyr) and intermediates (MIT, DIT) during thyroxine biosynthesis

8. Biosynthesis of T4 from DIT
Next reaction of DIT leads probably to creation reactive radical of DIT
This reactive radical condensates with other DIT residue and generates thyroxine residue (bound in thyreoglobulin)
Under normal condition 70% of tyrosine residues of thyreoglobulin are in the form MIT and DIT and 30% as thyroxine (with minor part of T3)

9. Schematic draw of condensation of DIT

10. Secretion of thyroid hormones
Endocytosis of iodinated thyreoglogulin from lumen into the cell
Fusion of endocytic vesicles with primary lysosomes
Degradation of thyreoglobulin in secondary lysosomes and liberating T3 a T4 into the circulation out of cell
70% of iodine bound by threoglobulin is in the form MIT and DIT and after liberation from thyreoglobulin these compounds are deionidated by enzyme deionidase and tyrosine and iodide is returned to further utilisation

12. Transport of thyroid hormones by blood
Thyroid hormones are hydrophobic compounds and therefore they used for its transport carrier protein
The main transporting protein is thyroxine binding globulin (TBG). Its affinity for T4 is 10 times higher than for T3 . The further proteins, binding thyroid hormones, are thyroxine binding prealbumin and albumin. More than 99% of T4 is bound on plasma proteins.
During this period the part of T4 is deionidated to T3 because this form is tentimes more metabolically active. Conversion of T4 to T3 is also observed in cytosol after transport into the target cell

13. Structural similarities among receptors for steroid and thyroid hormones

14. Mechanism of thyroid hormone action
Receptors for thyroid hormones are nuclear and its affinity is tentimes higher for T3 than T4
The amount of nuclear receptors is very low
Four variants of nuclear receptor were observed and mitochondrial receptor for T3 was also described
Free thyroid hormone receptor (TR) without bound hormone is bound to hormone response element of DNA (HRE) and corepressor (CoR)
After binding T3 to receptor - CoR is liberated and coactivators (CoA) is bound and the transcription to mRNA begins

15. Mechanism of thyroid hormone action

16. Increased expression of proteins by thyroid hormones
Glycerol 3-phosphate dehydrogenase – main component of glycerol 3-phosphate shuttle in mitochondria (one of transport systems for NADH into mitochondria)
Cytochrome c oxidase – the complex mitochondrial enzyme in the electron transport chain (from cytochrome c to oxygen)
ATPases – (eg. Ca ATPase of muscle cells)
Carbamyl phosphate synthase – enzyme of urea cycle
Growth hormone

17. Increased expression of proteins by thyroid hormones
Malic enzyme -
the enzyme utilizes nicotinamide-adenine dinucleotide (NAD+ ) to catalyze the oxidative decarboxylation of malic acid to pyruvic acid and carbon dioxide
the important enzyme of lipogenesis (key enzyme in the synthesis of fatty acids)

18. Increased respiration during hyperthyreodism
Increased synthesis of ATP – increased synthesis of cytochrome c oxidase – increased oxidative phosphorylation (it means the increased consumption of oxygen) – increased production of ATP
Increased consumption of ATP – increased synthesis of various ATPase (eg. Ca dependent in muscles) – increased depletion of store of ATP

19. Mechanisms increasing body temperature during hyperthyroidism
Reducing efficiency of ATP synthesis - increased synthesis of glycerol 3-phosphate dehydrogenase – increased transport NADH by this shuttle than malate/aspartate shuttle
Increased synthesis of ATP
Increased consumption of ATP
Uncoupling of phosphorylation and oxidation in mitochondria

20. Control of thyroid hormone synthesis and secretion
Pituitary hormone thyreotropin (TSH) upregulates activity of iodide pump of follicle cells of thyroid gland
Endocytosis of iodinated thyreoglobulin and following secretion of T3 and T4 is also upregulated by TSH
Production of TSH is upregulated by TRH and controled by thyroid hormones via negative feedback

21. Model of TSH receptor