Biochemistry of thyroid hormones
Vytášek 2010
3,5,3´-triiodothyronine (T3)
Thyroxine (T4)3,5,3´,5´-tetraiodothyronine
1)Biosynthesis of thyroid hormones andiodine metabolismus
2)Receptor for thyroid hormones andmechanisms of regulation of basalmetabolismus by thyroid hormones
3)Regulation of production of thyroidhormones, TSH, receptor of TSH, TRH
Biosynthesis of thyroxine
•The main synthetized thyroid hormone isthyroxine, but triiodothyronine is tentimes morepotent
•Precursor molecule for synthesis thyroidhormones is tyrosine derivative
•Biosynthesis is perfomed on tyrosine residuesbound in protein of thyroid gland – thyreoglobulin
•The first step is transport of iodide into cells offolicle cells of thyroid gland
•Active transport of iodide into the follicle cell ismediated iodide pump (the concentration outsideis 25times lower than inside)
Biosynthesis of thyroxine
•Thyreoglobulin, secreted into the lumen ofthyroid gland, is iodinated in one or twopositions of phenol ring of tyrosine residues
•Iodination reagent is iodosyl cation I+, vhichis produced by two electron oxidation ofiodide with hydrogen peroxide undercatalysis of enzyme thyroid peroxidase
•Electrophilic substitution of tyrosine ring byiodine in position 3 and 5 is pure chemicalreaction
Precursor molecule (Tyr) andintermediates (MIT, DIT) duringthyroxine biosynthesis
Biosynthesis of T4 from DIT
•Next reaction of DIT leads probably tocreation reactive radical of DIT
•This reactive radical condensates with otherDIT residue and generates thyroxine residue(bound in thyreoglobulin)
•Under normal condition 70% of tyrosineresidues of thyreoglobulin are in the formMIT and DIT and 30% as thyroxine (withminor part of T3)
Schematic draw of condensationof DIT
Secretion of thyroid hormones
•Endocytosis of iodinated thyreoglogulin fromlumen into the cell
•Fusion of endocytic vesicles with primarylysosomes
•Degradation of thyreoglobulin in secondarylysosomes and liberating T3 a T4 into thecirculation out of cell
•70% of iodine bound by threoglobulin is in theform MIT and DIT and after liberation fromthyreoglobulin these compounds are deionidatedby enzyme deionidase and tyrosine and iodide isreturned to further utilisation
Transport of thyroid hormones by blood
•Thyroid hormones are hydrophobic compounds andtherefore they used for its transport carrier protein
•The main transporting protein is thyroxine bindingglobulin (TBG). Its affinity for T4 is 10 times higher thanfor T3 . The further proteins, binding thyroid hormones, arethyroxine binding prealbumin and albumin. More than99% of T4 is bound on plasma proteins.
•During this period the part of T4 is deionidated to T3because this form is tentimes more metabolically active.Conversion of T4 to T3 is also observed in cytosol aftertransport into the target cell
Structural similarities amongreceptors for steroid and thyroidhormones
Mechanism of thyroid hormoneaction
•Receptors for thyroid hormones are nuclear and its affinityis tentimes higher for T3 than T4
•The amount of nuclear receptors is very low
•Four variants of nuclear receptor were observed andmitochondrial receptor for T3 was also described
•Free thyroid hormone receptor (TR) without boundhormone is bound to hormone response element of DNA(HRE) and corepressor (CoR)
•After binding T3 to receptor - CoR is liberated andcoactivators (CoA) is bound and the transcription tomRNA begins
Mechanism of thyroid hormone action
Increased expression of proteins bythyroid hormones
•Glycerol 3-phosphate dehydrogenase – maincomponent of glycerol 3-phosphate shuttle inmitochondria (one of transport systems for NADH intomitochondria)
•Cytochrome c oxidase – the complex mitochondrialenzyme in the electron transport chain (fromcytochrome c to oxygen)
•ATPases – (eg. Ca ATPase of muscle cells)
•Carbamyl phosphate synthase – enzyme of ureacycle
•Growth hormone
Increased respiration duringhyperthyreodism
Increased synthesis of ATP – increasedsynthesis of cytochrome c oxidase –increased oxidative phosphorylation (it meansthe increased consumption of oxygen) –increased production of ATP
Increased consumption of ATP – increasedsynthesis of various ATPase (eg. Cadependent in muscles) – increased depletionof store of ATP
Mechanisms increasing bodytemperature during hyperthyroidism
Reducing efficiency of ATP synthesis - increasedsynthesis of glycerol 3-phosphate dehydrogenase –increased transport NADH by this shuttle thanmalate/aspartate shuttle
Increased synthesis of ATP
Increased consumption of ATP
Uncoupling of phosphorylation and oxidation inmitochondria
Control of thyroid hormonesynthesis and secretion
•Pituitary hormone thyreotropin (TSH) upregulatesactivity of iodide pump of follicle cells of thyroidgland
•Endocytosis of iodinated thyreoglobulin andfollowing secretion of T3 and T4 is alsoupregulated by TSH
•Production of TSH is upregulated by TRH andcontroled by thyroid hormones via negativefeedback
Model of TSH receptor
Myxedema (myxoedema)
•Hypothyreoid myxedema is specific form of skinedema
•Increased activity of connective tissues leads toincreased deposition of components of extracellularmatrix (mainly glycosaminoglycans, proteoglycans)which retains large amounts of sodium ions and water
•Stimulation of fibroblasts is caused by increasedamount of TSH which is able to bind to somemembrane receptors and by this way it activatesbiosynthesis of extracellular matrix
Exophthalmos
bilateral exophthalmos (bulging eyes) is typicalmarker of autoimmune Graves' disease(hypethyreoidismus)
Thyroid-stimulating autoantibodies mimic theaction of TSH; they are directed against thethyrotropin receptor autoantigen (TSHR) onthe thyroid follicular cell and similarreceptors throughout the body and theymay also react with these autoantibodies
Subset of orbital fibroblasts is rich in thismembrane receptor
After stimulation the orbital fibroblasts arecapable of differentiating into adipocytesand thus increase orbital adipose tissue