1. The Thyroid

2. Thyroid hormones

5. 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

6. 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

7. + 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

8. 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

9. 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

10. 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

11. * * * * * 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)

12.   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

13. 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

14. Mechanism of thyroid hormone action

15. (e.g., pituitary/brain, liver, muscle, heart)
Circulating T4 - bound to TBG or TBPA
deiodination
T 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

16. Transport of thyroid hormones

17. 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)