1 / 18

The Thyroid

The Thyroid. Thyroid hormones. HO. CH 2 CHCOOH-. NH 2. SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION. HO. Tyr. TYROSINE. CH 2 CHCOOH-. THYROGLOBULIN. NH 2. TYROSINE IODINATION. I. Tyr. THYROGLOBULIN. MONOIODOTYROSINE (MIT).

garry
Download Presentation

The Thyroid

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The Thyroid

  2. Thyroid hormones

  3. HO CH2CHCOOH- NH2 SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION HO Tyr TYROSINE CH2CHCOOH- THYROGLOBULIN NH2 TYROSINE IODINATION I Tyr THYROGLOBULIN MONOIODOTYROSINE(MIT) 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 DIIODOTYROSINE (DIT) HO Tyr CH2CHCOOH - THYROGLOBULIN NH2 I

  4. I I I I I I 5’ 5 Tyr O Tyr Tyr 3’ 3 I I I T 4 I Tyr T 3 SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES I HO + HO HO CH2CHCOOH CH2CHCOOH Tyr HO NH2 NH2 I 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 3,5,3’-Triiodothyronine I I + CH2CHCOOH HO CH2CHCOOH Tyr HO O Tyr Tyr NH2 NH2 I I I Thyroglobulin I Thyroglobulin

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

  6. SECRETION OF THYROID HORMONE ENDOCYTOSIS OF ‘COLLOID’ IN FOLLICLE BY PSEUDOPOD 4 IODINATIONOF THYROGLOBULIN BY THYROID PEROXIDASE TG TG 3 TG I 5 FUSION OF PHAGOSOME WITH LYSOSOMES TG TG 6 DEGRADATION OF THYROGLOBULIN DEGRADATION AND RECYCLING OF MIT/DIT BY DEIODINASES 7 FREE THYROXINE RELEASED FROM PROTEIN INTO CYTOPLASM T4 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 Additional metabolism?? IODIDE IN ECF~20nM 1

  7. I I CH2CH-COOH CH2CH-COOH HO HO NH2 NH2 I 3-Monoiodotyrosine (MIT) 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

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

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

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

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

  12. Mechanism of thyroid hormone action

  13. Temp homeostasis: heat generation from ATP used by Na,K-ATPase in liver and other tissues Trans lation T3 T3 T3 T3 RXR RXR RXR RXR Trans-crip- tion mRNA O2 Circulating T4 - bound to TBG or TBPA deiodination T3 T4 5' deiodinase New Proteins (enzymes) Na+,K+-ATPase G3PDH Nucleus T3 receptor RNA Pol  O2 consumption Response element Induced gene Mitochondria 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

  14. Transport of thyroid hormones

  15. Table 2. A Summary of the Various Etiologies of Goiters.

More Related