OBJECTIVES Chemical nature of the thyroid hormones How different enzymes play a role in thyroid hormone formation? And what drugs affect them? Describe Metabolism of thyroid hormones
Thyroid hormones derived from two iodinated tyrosine molecules
This follicle lacks TSH stimulationThis follicle has been stimulated by high TSH
Synthesis of thyroid hormonesActive uptake of iodide into follicular cell Iodide iodine - H2O 2 (catalysed by TPO) Active uptake of iodine at follicular/ colloid interface Incorporation of iodine onto tyrosine residues of thyroglobulin Coupling of iodinated tyrosines Storeage of T3 and T4
Derivatives of aminoacid Tyrosine Tyrosine Thyroid hormones Catacholamines Steroid hormones
O
OH
I
I
I
I
OH
O
NH2
Thyroxine (T4)
O
OH
I
I
I
OH
O
NH2
3,5,3’-Triiodothyronine (T3) THYROID HORMONES
Active transport of iodine (ATPase dependent) against electrical and chemical gradient - concentration of iodine 30-50 times that of the circulation
Active uptake of iodine by a sodium iodide symporter
Oxidation of iodide to iodine Iodination of tyrosine residues at apical/colloid interface to form MIT and DIT Uptake of thyroglobulin into the lumen of the follicleIncorporation of iodine onto tyrosine residues on the thyroglobulin molecule
4) Release of T4 and T3 into circulation - 100g T4 & 10g T3/day3) ~ 10% T4 undergoes mono-deiodination to T3 before secretion2) Fusion of colloid droplets with lysosomes --> hydrolysis and release of thyroid hormones1) Stimulated by TSH colloid droplets with the bound thyroid hormones are taken back into follicular cells by pinocytosisConcentration of Iodide (I-) ACTIVE TRANSPORT BY THYROIDAL (I-) TRANSPORTER LINKED WITH Na+/I+ ATPASE Inhibition Perchlorate (ClO-4) Thiocyanate (SCN-)
Oxidation of iodide (I- I)Iodide Iodine Thyroid peroxidase & H2O2Inhibitor Propylthiouracil
Ion transport by the Thyroid follicular cell
I-I
organification
Propylthiouracil (PTU) blocks iodination of thyroglobulin
COLLOID
BLOOD
NaI symporter (NIS)
Thyroid peroxidase (TPO)
ClO4-, SCN-
Iodination of tyrosine (Organification) Oxidized Iodine + tyrosine residues ( thyroglobulin) MIT and DIT Peroxidase Inhibitor Thioureas
DIT + DIT Thyroxine (T4) Thyroperoxidase DIT + MIT Triiodothyronineine (T3)
Coupling of Iodotyrosyls
Inhibitor PropylthiouracilThyroperoxidase
5’ 5
3’ 35’ 5
Thyroid hormone metabolism
Metabolism of thyroid hormones
Series of deiodinations by deiodinasesType 1 - liver, kidney, thyroid, pituitary gland, CNS: 5’ and 5 positionsType 2 - brain, brown fat, placenta, pituitary gland: 5’ position only: T4 T3 only: intracellular concentrations of T3Type 3 - brain, placenta: 5 position only T4 T3Other metabolic pathways: sulphation, decarboxylation, conjugated with glucuronideControl of thyroid hormone synthesis and release and feedback control
TSH Receptors
TSH G protein linked receptor cAMP IP3 + DAG Protein Ca2+ Protein Kinase A CM Kinase C(high concentrations)
Actions of TSH Active uptake of iodine* Stimulates other reactions involved in thyroid hormone synthesis Stimulates the uptake of colloid Induces growth of the thyroid gland
Thyroid hormone receptors
Thyroid hormone receptorsType 2 receptors in nucleus - high affinity for T3 Dimerize with another T3 receptor (homodimer) or retinoic acid receptor (heterodimer) Dimerized receptor + other transcription factors gene transcription Membrane receptors? Ion movements
Isoforms of the thyroid hormone receptor
DBDDBD
DBD
DBD
T3
Dimerization of thyroid hormone receptors and gene activation/inactivation
Structural similarities among receptors for steroid and thyroid hormones
Mechanism of thyroid hormone actionReceptors for thyroid hormones are nuclear and its affinity is tentimes higher for T3 than T4 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)
Mechanism of thyroid hormone action
Increased expression of proteins by thyroid hormonesGlycerol 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 ATPIncreased consumption of ATP – increased synthesis of various ATPase (eg. Ca dependent in muscles) – increased depletion of store of ATPMechanisms 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 shuttleIncreased synthesis of ATPIncreased consumption of ATPUncoupling of phosphorylation and oxidation in mitochondriaControl 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