The Thyroid

The Thyroid

Thyroid hormones

Two hormones

• Tri-iodothyronine (T3)

• Tetra-iodothyronine (T4) = thyroxine

I I

HO O CH2-CH(NH2)-COOH

I

I

N.B. Reverse T3

TYROSINE IODINATION

CH2CHCOOH-

NH2

HO TyrTYROSINE

CH2CHCOOH

HO

CH2CHCOOH-

NH2

HOMONOIODOTYROSINE (MIT)

DIIODOTYROSINE (DIT)

I

I

NH2

TYROSINE IODINATION

I

I

SYNTHESIS OF THYROID HORMONES: STEP 1 - IODINATION

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.

Tyr

Tyr

THYROGLOBULIN

THYROGLOBULIN

THYROGLOBULIN-

Thyroglobulin

CH2CHCOOH

Thyroglobulin

I

I

Tyr

3,5,3’5’-tetraiodothyronine

SYNTHESIS OF THYROID HORMONES: STEP- 2 COUPLING OF IODOTYROSINES

CH2CHCOOH

NH2

+HO

II

I

Tyr

NH2

T4

Thyroglobulin

I

I

Tyr CH2CHCOOH

NH2

CH2CHCOOH

I

Tyr

NH2

Thyroglobulin

Tyr

II

I

Tyr O

+

IT3

3,5,3’-Triiodothyronine

Coupling of iodotyrosine moities results in the loss of the peptide linkage to thyroglobulin allowing thyroid hormones to diffuse across the cell membrane

II

Tyr

II

I

Tyr O

I

33’

5 5’

HO

HO

HO

HO

HO

3,5,3’5’-tetraiodothyronine

CH2CHCOOH

NH2

CH2CHCOOH

3,3’,5’-Triiodothyronine (reverse T3)

NH2

Tyr

II I

Tyr O

rT3

I

3,5,3’-Triiodothyronine (T3)

II

Tyr

II

I

Tyr O

T4I

T3

Tyr

II I

Tyr O

I

5’- deiodination5-deiodination

CH2CHCOOH

“ACTIVATION” PATHWAY“DEACTIVATION” PATHWAY

NH2

STEP 3

DEIODINATION

SELENODEIODINASES

TG

SECRETION OF THYROID HORMONEIODINATION OF THYROGLOBULIN

BY THYROID PEROXIDASE

“DIFFUSION” OF THYROXINE THROUGH CELL MEMBRANE

DEGRADATION OF THYROGLOBULIN

FUSION OF PHAGOSOME WITH LYSOSOMES

ENDOCYTOSIS OF ‘COLLOID’ IN FOLLICLE BY

PSEUDOPOD

TG

TG

TG

T4

T4 T3>> >

I

IODIDE UPTAKEBY Na/I

SYMPORTER

IODIDE IN ECF~20nM

DEGRADATIONAND

RECYCLINGOF MIT/DIT

BY DEIODINASES

Other monovalent anions compete with iodide for uptake; sometimes with useful medical and experimental applications e.g.

TCO 4;Cl0 4; SCN;

FREE THYROXINE RELEASED FROM PROTEIN INTO CYTOPLASM

TG

2

1

3

4

5

6

7

8

Additional metabolism??

CH2CH-COOH

NH2I

I

HO

3,5-Diiodotyrosine (DIT)

CH2CH-COOH

NH2

I

HO

3-Monoiodotyrosine (MIT)

Figure 2. Structures of MIT and DIT.

Precursors that when coupled together form thyroid hormonesDIT + DIT = T4 MIT + DIT = T3

IODINETrace elementThyroid gland concentrates iodine – contains 90% of body poolIodine transported and taken up as iodide ion

II

CH2CH-COOH

NH2

O

I I

HO

3,5,3',5'-Tetraiodothyronine (T4)most abundant form

Inactivation infasting adult

5-deiodinase

CH2CH-COOH

NH2

O

I

I I

HO

3,3',5'-Triiodothyronine (reverse) (rT3)inactive form

5'-deiodinase

Activation infed adult

Peripheraltargettissue

3,5,5'-Triiodothyronine (T3)most potent form

CH2CH-COOH

NH2

O

I

I I

HO

Figure 1. Chemistry and interconversions of the thyroid hormones

SecondaryLysosomes

Iodination

Peroxidase Peroxidase

DITTgb

DIT

DITDIT

DITMIT

MITMIT

MIT

Tgb

Tgb

I-

I+

Coupling

DITTgb

DIT

DITMIT

T3 MIT

DITT4

T4

TSH Secretion

TRH

Adenylylcyclase

TSH ReceptorSymport

*

I-

I-Na+

Na+

TgbTyr

Tyr

Extracellular Space (COLLOID)

THYROID FOLLICULAR CELL

Oxidation/H2O2

Secreted to Colloid

Tgb mRNA

Tgb

Tyr

Tyr

Protein synthesis

Tyrosine + otheramino acids

T4,T3

MITDIT

Protease-Hydrolysis

Diffusion

T4,T3

Release

PKA

cAMP

Increasedcell growth

Lysosomes

Na+/K+-ATPase

K+

Na+

Extracellular Space (BLOOD SIDE)

Figure 3. Iodine metabolism in the thyroid follicle and its stimulation by TSH

Mitochondrion

H2O2

O2 + H+

NADPHNADP+

Concentration

Deiodination

Thyroid-specific deiodinase

LATS/TSI

Tgb* * *

*

TSH

Peroxidase

Peroxidase

PeroxidaseIn Golgi

T4 T3

T4 T3

PKAactivation

PROTEINPHOSPHORYLATION

Cell GrowthSecretion of Thyroid

HormoneT4

Hypothalamus

Figure 4. The TRH-TSH- T4 axis

TRH

sensitivity to TRH

Thyroid

Thyrotroph (via IP3/Ca2+

and DAG)

TRHTSH

FSH

LH

hCG

FSH

LH

TSH

PlacentaCG

Pit

uitary

TSH

ATP cAMPAdenylylCyclase

THYROID HORMONES

HORMONERELATIVE 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)

PLASMACONCENTRATION

0.3 99.7

Mechanism of thyroid hormone action

.Mito.

Response

T3

nucleus

T3 DNAR

mRNA

plasma membrane

T3T4

T4

mito. ?

Thyroid Target Cell(e.g., pituitary/brain, liver, muscle, heart)

T3 receptor

RNA Pol

Nucleus

Inducedgene

Responseelement

New Proteins(enzymes)

mRNA

Trans-crip-tion

Trans

latio

n

Circulating T4 - bound to TBG or TBPA

G3PDH

Mitochondria

deiodinationT3 T4 5' deiodinase

RXR T3Na+,K+-ATPase

Temp homeostasis: heat generation from ATP used by Na,K-ATPase in liver and other tissues

O2

O2 consumption

Figure 5. Action of the thyroid hormones

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

RXR T3RXR T3RXR T3

Transport of thyroid hormones

T3/T4

thyroid

Bound>99%

freeblood

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)