The Thyroid

Thyroid hormones

MONOIODOTYROSINE (MIT) SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION SELENOIODINASES SELENOIODINASES TYROSINE HO Tyr CH2CHCOOH- THYROGLOBULIN NH2 TYROSINE IODINATION I CH2CHCOOH- NH2 HO MONOIODOTYROSINE (MIT) Tyr THYROGLOBULIN Approximately 10% of the tyrosine residues on the 550 amino acid residue Thyroglobulin molecule may become iodinated by the enzyme - thyroid peroxidase acting on the colloid at the luminal surface of the thyroid follicle. These reactions only occur in the thyroid at specific residues in “Hormonogenic” sites located at the extreme ends of the Thyroglobulin molecule. TYROSINE IODINATION I I Approximately 10% of the tyrosine residues on the 550 amino acid residue Thyroglobulin molecule may become iodinated by the enzyme - thyroid peroxidase acting on the colloid at the luminal surface of thyroid follicle. These reactions only occur in the thyroid at specific residues in “hormonogenic” sites located at the extreme ends of the Thyroglobulin molecule. DIIODOTYROSINE (DIT) HO Tyr CH2CHCOOH - THYROGLOBULIN NH2 I

3,5,3’5’-tetraiodothyronine SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES I I Tyr I Tyr O 3 3’ 5 5’ HO + HO Tyr CH2CHCOOH HO CH2CHCOOH HO NH2 NH2 I T 4 Thyroglobulin Thyroglobulin 3,5,3’5’-tetraiodothyronine Coupling of iodotyrosine moities results in the loss of the peptide linkage to thyroglobulin allowing thyroid hormones to diffuse across the cell membrane I Tyr 3,5,3’-Triiodothyronine I I + HO CH2CHCOOH CH2CHCOOH Tyr HO O NH2 NH2 Tyr Tyr I I Thyroglobulin Thyroglobulin I T 3 I

+ STEP 3 DEIODINATION T4 SELENODEIODINASES rT3 T T3 4 Tyr CH2CHCOOH Tyr NH2 NH2 I I Thyroglobulin 3,5,3’5’-tetraiodothyronine STEP 3 DEIODINATION I I I I Tyr O CH2CHCOOH Tyr NH2 I I I I I I “DEACTIVATION” PATHWAY T4 “ACTIVATION” PATHWAY 5-deiodination 5’- deiodination Tyr O Tyr SELENODEIODINASES rT3 I I T 4 I I I T3 I I I SELENOIODINASES I Tyr O Tyr CH2CHCOOH Tyr O Tyr CH2CHCOOH NH2 Tyr NH2 I I 3,3’,5’-Triiodothyronine (reverse T3) 3,5,3’-Triiodothyronine (T3) I

SECRETION OF THYROID HORMONE ENDOCYTOSIS OF ‘COLLOID’ IN FOLLICLE BY PSEUDOPOD 4 IODINATION OF THYROGLOBULIN BY THYROID PEROXIDASE TG 3 TG TG I 5 FUSION OF PHAGOSOME WITH LYSOSOMES TG TG 6 DEGRADATION AND RECYCLING OF MIT/DIT BY DEIODINASES DEGRADATION OF THYROGLOBULIN 7 T4 FREE THYROXINE RELEASED FROM PROTEIN INTO CYTOPLASM 2 8 Other monovalent anions compete with iodide for uptake; sometimes with useful medical and experimental applications e.g. TCO4;Cl04; SCN; IODIDE UPTAKE BY Na/I SYMPORTER “DIFFUSION” OF THYROXINE THROUGH CELL MEMBRANE T4 > > > T3 IODIDE IN ECF~20nM Additional metabolism?? 1

DIT + DIT = T4 MIT + DIT = T3 IODINE CH2CH-COOH NH2 I HO 3-Monoiodotyrosine (MIT) CH2CH-COOH NH2 I HO 3,5-Diiodotyrosine (DIT) Figure 2. Structures of MIT and DIT. Precursors that when coupled together form thyroid hormones DIT + DIT = T4 MIT + DIT = T3 IODINE Trace element Thyroid gland concentrates iodine – contains 90% of body pool Iodine transported and taken up as iodide ion

3,5,3',5'-Tetraiodothyronine (T4) most abundant form Inactivation in CH2CH-COOH NH2 O I HO 3,5,3',5'-Tetraiodothyronine (T4) most abundant form Inactivation in fasting adult 5-deiodinase CH2CH-COOH NH2 O I HO 3,3',5'-Triiodothyronine (reverse) (rT3) inactive form I I 5'-deiodinase Activation in fed adult Peripheral target tissue 3,5,5'-Triiodothyronine (T3) most potent form CH2CH-COOH NH2 O I HO Figure 1. Chemistry and interconversions of the thyroid hormones

* * * * * T4,T3 T4,T3    Extracellular Space (COLLOID) Figure 3. Iodine metabolism in the thyroid follicle and its stimulation by TSH DIT Tgb MIT Coupling DIT Tgb MIT T3 T4 Tgb Tyr I+ Oxidation/H2O2 Iodination I- Tgb Peroxidase Peroxidase * Peroxidase * * Secreted to Colloid THYROID FOLLICULAR CELL Tgb mRNA Tyr Protein synthesis Tyrosine + other amino acids Tgb H2O2 O2 + H+ NADPH NADP+ Peroxidase In Golgi Peroxidase Lysosomes Increased cell growth Tgb Mitochondrion Secondary Lysosomes PKA cAMP T4,T3 MIT DIT Protease- Hydrolysis Deiodination Thyroid-specific deiodinase * I- I - Na + Na+/K+-ATPase K+ Na+ Adenylyl cyclase Diffusion T4,T3 Release TSH Receptor Symport Concentration TSH LATS/TSI  *  TSH Secretion TRH  Extracellular Space (BLOOD SIDE)

  TRH  sensitivity to TRH T4  T3 Hypothalamus TRH TSH FSH LH hCG  LH TSH Placenta CG Pituitary Thyrotroph (via IP3/Ca2+ and DAG) TSH Thyroid ATP cAMP Adenylyl Cyclase PKA activation PROTEIN PHOSPHORYLATION Secretion of Thyroid Hormone Cell Growth T4 Figure 4. The TRH-TSH- T4 axis

VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION THYROID HORMONES HORMONE RELATIVE POTENCY PRODUCTION t½ (µg/day) 4-8 (24)* BOUND TO PLASMA PROTEINS (%) - 99.95 (days) 80- 90 8 0.04 99.8 0.1 + + + + rT3 VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION 2-3 (27) * 1-3 6-7 + T4 T3 * (µg/dL) CONCENTRATION 0.3 99.7

Mechanism of thyroid hormone action

(e.g., pituitary/brain, liver, muscle, heart) Circulating T4 - bound to TBG or TBPA deiodination T3 T4 5' deiodinase New Proteins (enzymes) Trans lation Temp homeostasis: heat generation from ATP used by Na,K-ATPase in liver and other tissues Na+,K+-ATPase RXR T3 Nucleus G3PDH RXR T3 T3 receptor RXR T3 RXR T3 RNA Pol Trans-crip- tion Response element  O2 consumption Induced gene O2 Mitochondria mRNA Other effects of T3:  brain development, myelination  Growth (GH transcribed in somatotrope; induction of anabolic enzymes)  TSH in thyrotrope (repressive pituitary effect)  1-adrenergic receptor Thyroid Target Cell (e.g., pituitary/brain, liver, muscle, heart) Figure 5. Action of the thyroid hormones

Transport of thyroid hormones

Table 2. A Summary of the Various Etiologies of Goiters. Hyperthyroid* excess T4 Hypothyroid** insufficient T4  TRH (tumor)  Nutritional iodine deficiency (TSH from feedback break)  TSH (tumor)  Defective thyroid: i) iodide uptake ii) peroxidase iii) deiodinase TSI/LATS (autoimmune activator of the TSH receptor)  Hashimoto’s Thyroiditis (autoimmune destruction of the thyroid)