1. BIOCHEMISTRY OF THYROID HORMONES ENDOCRINE SYSTEM, 2009 NABIL BASHIR

2. OUTLINES Chemistry of Thyroid Hormones Synthesis and Secretion of Thyroid Hormones Mechanism of Action Control of Thyroid Hormone Synthesis and Secretion

4. II CH 2 CH-COOH NH 2 O I I HO 3,5,3',5'-Tetraiodothyronine (T 4 ) most abundant form Inactivation in fasting adult 5-deiodinase CH 2 CH-COOH NH 2 O I I I HO 3,3',5'-Triiodothyronine (reverse) (rT 3 ) inactive form 5'-deiodinase Activation in fed adult Peripheral target tissue 3,5,3'-Triiodothyronine (T 3 ) most potent form CH 2 CH-COOH NH 2 O I I I HO Figure 1. Chemistry and interconversions of the thyroid hormones

5. CH 2 CH-COOH NH 2 I I HO 3,5-Diiodotyrosine (DIT) CH 2 CH-COOH NH 2 I HO 3-Monoiodotyrosine (MIT) Figure 2. Structures of MIT and DIT. Precursors that when coupled together form thyroid hormones DIT + DIT = T 4 MIT + DIT = T 3 IODINE Trace element Thyroid gland concentrates iodine – contains 90% of body pool Iodine transported and taken up as iodide ion

8. Secondary Lysosomes Iodination Peroxidase DIT Tgb DIT MIT Tgb I-I- I+I+ Coupling DIT Tgb DIT MIT T3T3 DIT T4T4 T4T4 TSH Secretion TRH Adenylyl cyclase TSH Receptor Symport * I-I- I - Na + + Tgb Tyr Extracellular Space (COLLOID) THYROID FOLLICULAR CELL Oxidation/H 2 O 2 Secreted to Colloid Tgb mRNA Tgb Tyr Protein synthesis Tyrosine + other amino acids T 4,T 3 MIT DIT Protease- Hydrolysis Diffusion T 4,T 3 Release PKA cAMP Increased cell growth Lysosomes Na + /K + - ATPase K+K+ Na + Extracellular Space (BLOOD SIDE) Figure 3. Iodine metabolism in the thyroid follicle and its stimulation by TSH Mitochondrion H2O2H2O2 O 2 + H + NADPH NADP + Concentration Deiodination Thyroid-specific deiodinase LATS/TSI    Tgb * ** * TSH Peroxidase In Golgi

10. Biosynthesis of Thyroid Hormones

13. Mechanism of Action of Thyroid Hormones Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-responsive transcription factors, very similar conceptually to the receptors for steroid hormones.

14. Thyroid hormones enter cells through membrane transporter proteins. Once inside the nucleus, the hormone binds its receptor, and the hormone-receptor complex interacts with specific sequences of DNA in the promoters of responsive genes. The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes.

15. Thyroid Target Cell (e.g., pituitary/brain, liver, muscle, heart) T 3 receptor RNA Pol Nucleus Induced gene Response element New Proteins (enzymes) mRNA Trans- crip- tion Trans lation Circulating T 4 - bound to TBG or TBPA G3PDH UCP Mitochondria deiodination T 3 T 4 5' deiodinase RXR T3T3 Na +,K + - ATPase Temp homeostasis: heat generation from ATP used by Na,K- ATPase in liver and other tissues O2O2  O 2 consumption  BMR (liver) Figure 5. Action of the thyroid hormones Other effects of T 3 :  brain development, myelination  Growth (GH transcribed in somatotrope; induction of anabolic enzymes)  TSH in thyrotrope (repressive pituitary effect)   1 -adrenergic receptor RXR T3T3 T3T3 T3T3

16. Symptom of Hyperthyroidism Affected Enzyme, Receptor, Hormone, Antibody, etc. Symptom of Hypothyroidism  Weight  BMR Mitochondrial Uncoupling Protein (UCP), Oxidative Enzymes  Weight  BMR Heat IntoleranceUCP, Na/K-ATPaseCold Intolerance  Heart RateCardiac  1 -Adrenergic Receptor  Heart Rate IrritableCentral Sympathetic  -Adrenergic Receptor Sluggish Moist SkinFluid ImbalanceDry Skin ExophthalmosThyroid Stimulating Immunoglobulin (TSI) ------ GoiterTSI or TSHGoiter ------Myelin  Mental Development ------Growth Hormone  Growth Table 1. Biochemical Basis for the Symptoms of Hyper- and Hypothyroidism.

18. Control of Thyroid Hormone Synthesis and Secretion Each of the processes described above appears to be stimulated by thyroid-stimulating hormone TSH from the anterior pituitary gland. Binding of TSH to its receptors on thyroid epithelial cells stimulates synthesis of the iodine transporter, thyroid peroxidase and thyroglobulin. TSH controls the rate of endocytosis of colloid - high concentrations of TSH lead to faster rates of endocytosis, and hence, thyroid hormone release into the circulation. Conversely, when TSH levels are low, rates of thyroid hormone synthesis and release diminish.

20. Lipid metabolism: increased concentrations of fatty acids in plasma. increased oxidation of fatty acids in many tissues. Decreased cholesterol and triglycerides

21. Carbohydrate metabolism: enhancement of insulin-dependent entry of glucose increased gluconeogenesis glycogenolysis

22. Pathology of the thyroid gland function Hypothyroidism is the result from any condition that results in thyroid hormone deficiency. Two well-known examples include: Iodine deficiency: Goiter Primary thyroid disease: Inflammatory diseases of the thyroid that destroy parts of the gland are clearly an important cause of hypothyroidism.

25. Hyperthyroidism Graves disease, an immune disease in which autoantibodies bind to and activate the thyroid-stimulating hormone receptor, leading to continual stimulation of thyroid hormone synthesis.