BIOCHEMISTRY OF THYROID HORMONES

ENDOCRINE SYSTEM, 2009

NABIL BASHIR

OUTLINES

• Chemistry of Thyroid Hormones

• Synthesis and Secretion of Thyroid Hormones

• Mechanism of Action

• Control of Thyroid Hormone Synthesis and Secretion

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

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

CH2CH-COOH

NH2

O

I

I I

HO

Figure 1. Chemistry and interconversions of the thyroid hormones

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

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

Biosynthesis of Thyroid Hormones

Mechanism of Action of Thyroid Hormones

• Receptors for thyroid hormones are intracellular DNA-binding proteins that function as hormone-responsive transcription factors, very similar conceptually to the receptors for steroid hormones.

• Thyroid hormones enter cells through membrane transporter proteins.

• Once inside the nucleus, the hormone binds its receptor, and the hormone-receptor complex interacts with specific sequences of DNA in the promoters of responsive genes.

• The effect of the hormone-receptor complex binding to DNA is to modulate gene expression, either by stimulating or inhibiting transcription of specific genes.

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

UCP

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 BMR (liver)

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

Symptom of Hyperthyroidism

Affected Enzyme, Receptor, Hormone, Antibody, etc.

Symptom of Hypothyroidism

WeightBMR

Mitochondrial Uncoupling Protein (UCP), Oxidative Enzymes

WeightBMR

Heat Intolerance UCP, Na/K-ATPase Cold Intolerance

Heart Rate Cardiac 1-Adrenergic

Receptor

Heart Rate

Irritable Central Sympathetic-Adrenergic Receptor

Sluggish

Moist Skin Fluid Imbalance Dry Skin

Exophthalmos Thyroid Stimulating Immunoglobulin (TSI)

------

Goiter TSI or TSH Goiter

------ Myelin Mental Development

------ Growth Hormone Growth

Table 1. Biochemical Basis for the Symptoms of Hyper- and Hypothyroidism.

Control of Thyroid Hormone Synthesis and Secretion

• Each of the processes described above appears to be stimulated by thyroid-stimulating hormone TSH from the anterior pituitary gland.

• Binding of TSH to its receptors on thyroid epithelial cells stimulates synthesis of the iodine transporter, thyroid peroxidase and thyroglobulin.

• TSH controls the rate of endocytosis of colloid - high concentrations of TSH lead to faster rates of endocytosis, and hence, thyroid hormone release into the circulation.

• Conversely, when TSH levels are low, rates of thyroid hormone synthesis and release diminish.

Lipid metabolism:

• increased concentrations of fatty acids in plasma.

• increased oxidation of fatty acids in many tissues.

• Decreased cholesterol and triglycerides

Carbohydrate metabolism:

• enhancement of insulin-dependent entry of glucose

• increased gluconeogenesis glycogenolysis

Pathology of the thyroid gland function

Hypothyroidism is the result from any condition that results in thyroid hormone deficiency. Two well-known examples include:

• Iodine deficiency: Goiter• Primary thyroid disease: Inflammatory

diseases of the thyroid that destroy parts of the gland are clearly an important cause of hypothyroidism.

• Hyperthyroidism

• Graves disease, an immune disease in which autoantibodies bind to and activate the thyroid-stimulating hormone receptor, leading to continual stimulation of thyroid hormone synthesis.