BIOCHEMISTRY OF HORMONE

Dr. Novi Khila Firani, Mkes., SpPK

Biochemistry-Biomolecular Laboratory
University of Brawijaya
Hormone ?
 = substance that is
synthesized in one organ and
transported by the circulatory
system to act on another
tissue
 hormones can act on adjacent
cells (paracrine action) and on
the cell in which they were
synthesized (autocrine
action) without entering the
systemic circulation.
Hormone’s target cell
 A target cell is defined by its ability to selectively bind a
given hormone

Specificity and
selectivity of
hormone receptors

 Hormone’s receptors are Proteins :

 intracellular receptors
 cell surface receptors
Determinants of the concentration
of a hormone at the target cell

 The rate of synthesis and secretion of the hormones.

 The proximity of the target cell to the hormone source
(dilution effect).
 The dissociation constants of the hormone with specific
plasma transport proteins (if any).
 The conversion of inactive forms of the hormone into the
fully active form.
 The rate of clearance from plasma by other tissues or by
digestion, metabolism, or excretion.
Classification of hormones

Chemical composition

Mechanism of action/
location of receptor

Solubility properties
Classification of hormones based on
chemical composition

 Cholesterol derivatives
 Tyrosine derivatives  T3, T4
 Peptides  Insulin
 Glycoprotein
Cholesterol derivatives hormone

The basic sterol rings

Tyrosine derivative hormones
 Classification of hormones by mechanism of action

I. Hormones that bind to intracellular receptors

II. Hormones that bind to cell surface receptors :
A. The second messenger is cAMP
B. The second messenger is cGMP
C. The second messenger is calcium or phosphatidylinositols
(or both)
D. The second messenger is a kinase or phosphatase cascade
General features of hormone classes
Two general mechanisms of hormone action

Cell
surface
receptor

Intracellular
receptor
Hormonal involvement in responses to a stimulus
I. Hormones that bind to intracellular receptors
 Androgens
 Calcitriol (1,25[OH]2-D3)
 Estrogens
 Glucocorticoids
 Mineralocorticoids
 Progestins
 Retinoic acid
 Thyroid hormones (T3 and T4)
II. Hormones that bind to cell surface
receptors
II. Hormones that bind to cell surface
receptors
 Clinical Importances
HYPERTHYROID HYPOTHYROID

EXOPHTHALMUS
DIABETES MELLITUS  Hyperglycemia
The endocrine system of the pancreas
HORMONES OF THE PANCREAS

SOMATOSTATIN : REGULATES INSULIN AND GLUKAGON SECRETION

PANCREATIC POLIPEPTIDE : GASTROINTESTINAL SECRETION

 Structure of human proinsulin.
Insulin and C-peptide molecules are connected at two sites by dipeptide links.
Glucose regulation of insulin secretion by pancreatic
cells
Glucose Transporter(GLUT)

Harper’s Biochemistry
ROLE OF INSULIN :

1. Induce glycolysis
2. Inhibit gluconeogenesis
3. Increase glucose uptake  GLUT 4
4. Increase glycogenesis
5. Inhibit lipolysis
6. Increase protein synthesis
Effect of insulin

PFK=Phospho fructo kinase

Insulin signaling
Regulation by insulin of glucose transport by
GLUT4 into a myocyte

Lehninger Principles of Biochemistry, 2004

Glucose Transporter(GLUT)

Harper’s Biochemistry
GLYCOLYSIS REGULATION

Enzyme of Inducer Repressor Activator Inhibitor

glycolysis
Hexokinase Glucosa 6-
phosphate
Glucokinase Insulin Glucagon
(cAMP)

Phosphofructo Insulin Glucagon AMP, Pi, Fruc 6- ATP, Sitrat, Fatty

kinase-1 (cAMP) phosph, Fructose acid, Keton bodies,
2,6-biphosph Glucagon (cAMP)

Pyruvat kinase Insulin Glucagon Fruc 1,6 ATP, Glucagon

(cAMP) biphosphate, (cAMP),
Insulin Epinephrine

Harper’s Biochemistry
GLUCONEOGENESIS REGULATION
Enzyme of Inducer Repressor Activator Inhibitor
gluconeogenesis
Glucose -6- Glucagon Insulin
phosphatase Epinefrin
(cAMP)
Glucocorti
coid
Fructose-1,6- Idem Insulin Glucagon Fruc-1,6-
biphosphatase (cAMP) biphosphate,
Fruc-2,6
biphosphate,
AMP

PEP Idem Insulin

carboxykinase

Pyruvat Idem Insulin Acetyl CoA ADP

carboxylase

Harper’s Biochemistry
Regulation of PDH kinase and PDH fosfatase
GLYCOGENESIS
 ACTH, TSH, INSULIN
ADRENALINE GLUKAGON
NORADRENALINE
hormon sensitive
- Lipase (TG lipase)
ATP
Β-Blocker Adre- + + - ( inactive)
nalin
H. THYROID ADENYLATE + Insulin
+ -
CYCLASE Protein kinase
Lip. Fosfatase
-
INHIBITOR cAMP + (dependent - TG
GH -
ADENOSINE cAMP)

PHOSPHODIESTERASE
hormon sensitive
METIL XANTIN, - -
Lipase (TG lipase) FFA
CAFEIN, TEOFI – + 5AMP
LINE (active)
INSULIN +
- DG
H. THYROID
-
GLUKOKORTIKOID 2 FFA
Hormon sensitive lipase (TG Inhibitor
GLYCEROL
lipase) regulation in adipose
Glucagon’s Metabolic effect
Insulin and Glucagon actions
THYROID HORMONE
T3 : 3,5,3’-TRIIODOTHYRONINE
TYROSINE DERIVATE
T4 : 3,5,3’,5’-TETRAIODOTYRONINE (THYROXINE)

NEED TRACE ELEMENT : IODINE

Structure of
Thyroid Hormone

The thyroid hormones are

iodinated thyronines, which
are comprised of two tyrosine
moieties joined by an ether
linkage
Thyroid hormone synthesis occurs in the
follicular space
PRECURSOR OF T3 AND T4 : THYROGLOBULIN

PRODUCED BY FOLLICULAR CELLS OF THYROID GLAND

PRODUCTION STIMULATED BY TSH

PROTEIN 660 KDA, 5000 AMINO ACID

CONTAIN 115 TYROSINE RESIDUES FOR IODINATION

T4:T3 RATIO IN THYROGLOBULIN : 7:1

IOD DEFISIENSI : RATIO T4:T3 DECREASE
Thyroid Hormone Synthesis & Secretion

6 major steps:
1. active transport of I– across the basement membrane into
the thyroid cell (trapping);
2. oxidation of iodide and iodination of tyrosyl residues in
thyroglobulin (organification);
3. linking pairs of iodotyrosine molecules within
thyroglobulin to form the iodothyronines T3 and T4
(coupling);
4. proteolysis of thyroglobulin, with release of free
iodothyronines into the circulation;
5. deiodination of iodotyrosines within the thyroid cell, with
conservation and reuse of the liberated iodide;
6. intrathyroidal 5'-deiodination of T4 to T3.
IODIDE METABOLISM

- CONCENTRATION OF IODIDE : IOD PUMP

- OXIDATION OF IODIDE : I- TO I+

- IODINATION OF TYROSINE : 3 AND 5 POSITION

- COUPLING OF IODOTYROSIN : DIT+DIT : T4

MIT+DIT : T3
Thyroid Hormone Synthesis

PTU

NIS
Thyroid
Hormone
synthesis
 Thyroid hormone transport proteins
There are three major thyroid hormone transport proteins:
 thyroxine-binding globulin (TBG) : 70%
 transthyretin or thyroxine-binding prealbumin (TBPA) :
20%
 albumin (10%)

TBG : GLICOPROTEIN, 50 KDA 100X AFFINITY OF TBPA, NONCOVALENT

BINDS T3 AND T4 100 TIMES AFFINITY TO TBPA
MORE IMPORTANT THAN TBPA

PRODUCE IN THE LIVER

STIMULATES BY ESTROGEN (PREGNANT AND PILS)
DECREASE DURING ANDROGEN OR GLUCOCORTICOID TX
ONLY SMALL AMOUNT OF FREE T3 AND T4

FREE T3 T4 : IMPORTANT FOR BIOLOGIC ACTIONS

RATIO T3:T4 IN BLOOD PLASMA: 1:1

80% T4 CONVERTED TO T3 IN CIRCULATION (DEIODINATION)

T3 BINDS RECEPTOR 10 TIMES OF T4

T3 MORE IMPORTANT FOR BIOLOGIC ACTIVITY

THYROID HORMONE ACTION

ENHANCE PROTEIN SYNTHESIS

STIMULATION GLUCONEOGENESIS & GLYCOGENOLYSIS
ACCELERATED BREAKDOWN OF VLDL & LDL
ACCELERATED CHOLESTEROL CLEARANCE & LIPOLYSIS
INDUCE GH TRANSCRIPTION  IMPORTANT FOR DEVELOPMENT
Regulation of thyroid hormone synthesis
ELEVATED TSH

CAUSED BY :

IODIDE DEFICIENCY
IODIDE TRANSPORT DEFECT
IODINATION DEFECT
COUPLING DEFECT
DEIODINASI DEFICIENCY
PRODUCTION OF ABNORMAL IODINATION PROTEIN
 GOITER

TSH

THYROID HORMONE

IOD METABOLISM DEFECT

IOD DEFFICIENCY
HYPOTHYROIDISM

THYROID FAILURE/PITUITARY OR HYPOTHALAMUS DESEASE

INSUFFICIENT OF T3 AND T4

BASAL METABOLISM DECREASE, SLOW HEART RATE,

SLEEPNESS, CONSTIPATION

SENSITIVE TO COLD, DRY SKIN AND HAIR

CRETINISM
 HYPERTHYROIDSM
(GRAVE’S DESEASE)

UNCONTROLLED T3 T4 PRODUCTION

STIMULATION OR TSH RECEPTOR OF THYROID GLAND CELLS

THYROID STIMULATING IgG (TSI)

HYPERTHYROIDISM

RAPID HEART RATE (PALPITATION)

NERVOUSNESS

INABILITY TO SLEEP

INCREASE APPETITE

WEIGHT LOSS

EXCESSIVE SWEATING

SENSITIVE TO HEAT

WEAKNES

RED, MOIST SKIN

ANTITHYROID DRUGS THAT INHIBIT IOD OXIDATION STEP BY PEROXIDASE
References
 Murray R.K.; Granner D.K.; Mayes P.A.; Rodwell V.W.
Harper’s Biochemistry 27th ed. Appleton and Lange
Medical Publication U.S.A. 2006.
 Marks D.B.; Marks A.D.; Smith C.M, Basic Medical
Biochemistry : A Clinical Approach, 2nd edition,
Lippincott Williams & Wilkins. 2005
 Nelson, D.L., Cox Lehninger,WH Freeman, Lehninger’s
Principles of Biochemistry. 4th edition. 2004
 etc
THANK YOU