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The Thyroid
Thyroid hormones
Two hormones
• Tri-iodothyronine (T3)
• Tetra-iodothyronine (T4) = thyroxine
I
HO
I
O
CH2-CH(NH2)-COOH
I
I
N.B. Reverse T3
SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION
TYROSINE
TYROSINE
IODINATION
MONOIODOTYROSINE (MIT)
THYROGLOBULIN
I
THYROGLOBULIN
Tyr
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
DIIODOTYROSINE (DIT)
-
Tyr
NH2
I
THYROGLOBULIN
SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES
I
HO
I
CH2CHCOOH
Tyr
I
HO
5’
+ HO
Tyr
CH2CHCOOH
HO
I
Tyr
O
Tyr
3
T4
I
Thyroglobulin
Thyroglobulin
5
3’
NH2
NH2
I
II
I
3,5,3’5’-tetraiodothyronine
I
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
Tyr
HO
CH2CHCOOH
+
Tyr
CH2CHCOOH
NH2
NH2
HO
Tyr
O
Tyr
I
I
Thyroglobulin
Thyroglobulin
I
T3
I
3,5,3’5’-tetraiodothyronine
STEP 3
DEIODINATION
I
I
O
Tyr
CH2CHCOOH
Tyr
NH2
“DEACTIVATION” PATHWAY
I
T4
I
5’- deiodination
5-deiodination
rT3
I
Tyr
O
“ACTIVATION” PATHWAY
SELENODEIODINASES
I
T3
I
Tyr
CH2CHCOOH
Tyr
I
O
Tyr
NH2
I
3,3’,5’-Triiodothyronine (reverse T3)
CH2CHCOOH
NH2
I
3,5,3’-Triiodothyronine (T3)
SECRETION OF THYROID HORMONE
4
IODINATION OF THYROGLOBULIN
BY THYROID PEROXIDASE
TG
3
TG
TG
I
ENDOCYTOSIS OF
‘COLLOID’ IN FOLLICLE BY
PSEUDOPOD
5
FUSION OF PHAGOSOME
WITH LYSOSOMES
TG
DEGRADATION
AND
RECYCLING
OF MIT/DIT
BY DEIODINASES
6
TG
DEGRADATION OF
THYROGLOBULIN
7
T4
2
FREE THYROXINE RELEASED FROM
PROTEIN INTO CYTOPLASM
8
IODIDE UPTAKE
BY Na/I
SYMPORTER
“DIFFUSION” OF THYROXINE
THROUGH CELL MEMBRANE
T4> > > T3
1
IODIDE IN
ECF~20nM
Additional metabolism??
I
HO
I
CH2CH-COOH
CH2CH-COOH
HO
NH2
3-Monoiodotyrosine (MIT)
I
NH2
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
I
I
O
HO
5-deiodinase
NH2
I
I
3,5,3',5'-Tetraiodothyronine (T4)
most abundant form
Peripheral
target
tissue
O
HO
CH2CH-COOH
I
I
Inactivation in
fasting adult
CH2CH-COOH
NH2
I
3,3',5'-Triiodothyronine (reverse) (rT3)
inactive form
I
I
5'-deiodinase
HO
Activation in
fed adult
O
CH2CH-COOH
NH2
I
3,5,5'-Triiodothyronine (T3)
most potent form
Figure 1. Chemistry and interconversions of the thyroid hormones
Figure 3. Iodine metabolism in the thyroid follicle
and its stimulation by TSH
Extracellular Space (COLLOID)
MITMIT
Tyr DIT
Tyr
DIT
MIT Tgb DIT
Tgb
DIT
DITMIT Coupling
Iodination
+
Oxidation/H2O2 I
IPeroxidase
*
*
THYROID FOLLICULAR CELL
Tyr
Tgb
Peroxidase
Tgb
Peroxidase
In Golgi
Peroxidase
Peroxidase
*
Secreted to Colloid
Tyr
mRNA
O2 + H+ NADP+
NADPH
Lysosomes
Secondary
Lysosomes
Mitochondrion
Tyrosine + other
Thyroid-specific
amino acids
deiodinase
Na+
Deiodination
Symport Concentration
Na+
*
I-
Tgb
H2O2
Protein synthesis
I-
T3 MIT
DIT
DIT
MIT Tgb
T4
DIT
T4 DIT
*
K+
ProteaseHydrolysis
MIT
DIT
Diffusion
T4,T3
Na+/K+-
Na+ ATPase
Extracellular Space (BLOOD SIDE)
T4,T3
Release
Tgb
PKA
Tgb
Increased
cell growth
cAMP
Adenylyl
cyclase
TSH Receptor
LATS/TSI
 TSH

TSH
TRH

Secretion

T4  T3 Hypothalamus
 TRH
TRH

 sensitivity
to TRH
TSH
T4  T3 Thyrotroph (via IP3/Ca2+
FSH
and DAG)
LH
TSH
hCG
Thyroid
 TSH
 FSH
Pituitary
 LH
 CG
Placenta
ATP Adenylyl cAMP
PKA
activation
Cyclase
PROTEIN
PHOSPHORYLATION
T4
Secretion of Thyroid
Hormone
Figure 4. The TRH-TSH- T4 axis
Cell Growth
THYROID HORMONES
HORMONE
T4
T3
rT3
*
RELATIVE
POTENCY
+
++++
-
PRODUCTION
PLASMA
CONCENTRATION
(µg/day)
(µg/dL)
80- 90
8
4-8 (24)*
2-3 (27) *
BOUND TO
PLASMA
PROTEINS
(%)
99.95
t½
(days)
6-7
0.3
99.7
1-3
0.04
99.8
0.1
VALUES IN PARENTHESES INDICATE PERIPHERAL CONVERSION
Mechanism of thyroid hormone action
T4
T3
plasma membrane
T4
T3
nucleus
mito.
M
. ito. ?
Response
R T3
DNA
mRNA
Circulating T4 - bound to TBG or TBPA
deiodination
T3
5' deiodinase
T4
RXR T3
Nucleus
RXR TT33 receptor
RXR
T33
RXR T
New Proteins
(enzymes)
Trans
lation
G3PDH
Na+,K+ATPase
RNA Pol
Response Induced
element
gene
mRNA
Transcription
Temp homeostasis:
heat generation from
ATP used by Na,KATPase in liver and
other tissues
 O2 consumption
Mitochondria
Thyroid Target Cell
(e.g., pituitary/brain, liver, muscle, heart)
Figure 5. Action of the thyroid hormones
O2
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
Transport of thyroid hormones
thyroid
T3/T4
blood
free
Bound
>99%
target tissues
response
inactivation
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
(TSH from feedback break)
TSI/LATS
(autoimmune activator of the
TSH receptor)
 Hashimoto’s Thyroiditis
(autoimmune destruction of the
thyroid)
(TSH from feedback break)