Biochemistry of thyroid hormones Vytášek 2010

3,5,3´-triiodothyronine (T 3 )

Thyroxine (T 4 ) 3,5,3´,5´-tetraiodothyronine

1)Biosynthesis of thyroid hormones and iodine metabolismus 2)Receptor for thyroid hormones and mechanisms of regulation of basal metabolismus by thyroid hormones 3)Regulation of production of thyroid hormones, TSH, receptor of TSH, TRH

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)

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

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

Biosynthesis of T 4 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 T 3 )

Schematic draw of condensation of DIT

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

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 T 4 is 10 times higher than for T 3. The further proteins, binding thyroid hormones, are thyroxine binding prealbumin and albumin. More than 99% of T 4 is bound on plasma proteins. During this period the part of T 4 is deionidated to T 3 because this form is tentimes more metabolically active. Conversion of T 4 to T 3 is also observed in cytosol after transport into the target cell

Structural similarities among receptors for steroid and thyroid hormones

Mechanism of thyroid hormone action Receptors for thyroid hormones are nuclear and its affinity is tentimes higher for T 3 than T 4 The amount of nuclear receptors is very low Four variants of nuclear receptor were observed and mitochondrial receptor for T 3 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 T 3 to receptor - CoR is liberated and coactivators (CoA) is bound and the transcription to mRNA begins

Mechanism of thyroid hormone action

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

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

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

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 T 3 and T 4 is also upregulated by TSH Production of TSH is upregulated by TRH and controled by thyroid hormones via negative feedback

Model of TSH receptor

Myxedema (myxoedema) Hypothyreoid myxedema is specific form of skin edema Increased activity of connective tissues leads to increased deposition of components of extracellular matrix (mainly glycosaminoglycans, proteoglycans) which retains large amounts of sodium ions and water Stimulation of fibroblasts is caused by increased amount of TSH which is able to bind to some membrane receptors and by this way it activates biosynthesis of extracellular matrix

Exophthalmos bilateral exophthalmos (bulging eyes) is typical marker of autoimmune Graves' disease (hypethyreoidismus) Thyroid-stimulating autoantibodies mimic the action of TSH; they are directed against the thyrotropin receptor autoantigen (TSHR) on the thyroid follicular cell and similar receptors throughout the body and they may also react with these autoantibodies Subset of orbital fibroblasts is rich in this membrane receptor After stimulation the orbital fibroblasts are capable of differentiating into adipocytes and thus increase orbital adipose tissue