Biochemistry of

Hormones

SBP 3201
Dr. Sharifah Sakinah Syed Alwi
 Hormones

Hormone is defined as a substance that is

synthesized in one organ and transported by
circulatory system to act on a another tissue
 Hormones are chemically diverse
• Cholesterol derived hormones- .
– Glucocorticoids
– Mineralocorticoids
– Estrogen
– Progestins

• Steroid hormones can be the precursor of

another hormone-
– Progesterone is the precursor of mineralocorticoids,
glucocorticoids and androgens
• Some hormones are synthesized in the final form and
secreted immediately
– Cholesterol derived hormones

• Other hormones are synthesized in the final form and stored

in the producing cells
– Catecholamines

• There are hormones synthesized from their precursor

molecules, processed and then secreted upon physiologic
responses
– Insulin

• Hormones can be classified according to

– Chemical composition, solubility properties, location of receptors
• The amino acid tyrosine is the precursor of catecholamines
and of thyroid hormones
– Thyroid hormones require iodine addition for their bioactivity

• Many hormones are polypeptides

– E.g- ACTH (39AA), TRH (tripeptide), PTH (84AA) and
growth hormone (191AA)
Polypeptides
Insulin FSH Oxytocin
glucagon LH thyrotropin
somatotropin vasopressin ACTH

Steroids
Estrogen Aldosterone
testosterone corticosterone
cortisol Progesterone

Amino acid derivatives

Epinephrine Thyroxine, T3 and T4
norepinephrine Melatonin
dopamine Serotonin
Rule: All hormones interact with target cells by first binding to
specific receptors located either on the plasma membrane or as a
cytosolic protein

Rule: The receptor for hormones must be linked to a component

that is able to respond to the binding of hormone with its receptor

Rule: Substances that fool the responder into thinking a

hormone has bound are call agonists

Rule: Substances that prevent the binding of the natural

hormone and do not elicit a response from the receptor are called
antagonists
 Releasing Hypothalamus
hormones
Anterior pituitary
Posterior pituitary
Thyrotropin
Somatotropin FSH Vasopressin
LH Prolactin Oxytocin
ACTH

Adrenal Adrenal
Thyroid Cortex Pancreas Ovary Testis Medulla

T3 Cortisol Insulin, Estradiol Testosterone Epinephrine

aldosterone glucagon,
somatostatin

Muscles Liver, Reproductive Mammary

liver Tissues muscles organs glands
 Feedback Loops
Rule: Hormones elicit their own shut off mechanism
Hypothalamus

Anterior
Pituitary
Corticotropin Adrenal
releasing factor + Cortex

-Corticotropin
+

Cortisol
Rule: All peptide hormones are synthesized as inactive “pre-
pro” precursors

Rule: A signal peptide must be cleaved off to activate the

mature form of the hormone
 Classification of hormones by
mechanism of action
• The following classification is based on the location
of receptors and the nature of signal produced;

Hormone that bind to Hormone that bind to cell

intracellular receptor surface receptor
- Steroid hormones enter the cell - Involve 2nd messenger
by simple diffusion across the - cAMP
plasma - cGMP
- Thyroid hormones enter the - Calcium/
cell by facilitated diffusion phosphatidylinositol
I. Hormones that bind to intracellular receptors:

i. Androgens
ii. Calcitriol
iii. Estrogens
iv. Progestins
v. Retinoic acid
vi. Glucocorticoids
vii. Mineralocorticoids
viii.Thyroid hormones
II. Hormones that bind to cell surface receptors

A. Second messenger is cAMP:

i. α2 adrenergic catecholamines
ii. β- adrenergic catecholamines
iii. ACTH
iv. ADH
v. Calcitonin
vi. FSH
vii. LH
viii. TSH
ix. Glucagon
x. Somatostatin
B. Second messenger is cGMP:
i. Atrial natriuretic factor
ii. Nitric oxide

C. Second messenger is calcium or

phosphatidylinositol:
i. Acetylcholine
ii. Angiotensin
iii. Gastrin
iv. TRH
v. Oxytocin
vi. ADH
vii. PDGF
 Hormones receptors
• Hormones are present in very low concentrations in the
extracellular fluid- 10-18 to 10-9 range

• Other molecules are present in millimoles and micromoles

range

• The cells have to distinguish between hormones and other

substances

• High degree of recognition is provided by cell associated

recognition molecules called receptors

• Hormones initiates their biologic effects by binding to specific

receptors
• A target cell is defined by its ability to selectively bind a given
hormones to its cognate receptor.

• Receptors have at least 2 functional domains

– A recognition domain- it binds to the hormone ligand
– Second region- that generates a signal when the hormones binds to it

• The dual function of binding and coupling (signal generation)

ultimately defines a receptor
 Chemical nature of receptor
• Receptors are proteins

• Several classes of peptide receptors have been identified

– E.g
• Insulin receptor
• It is heterotetramer composed of 2 different protein subunits (α2β2)
• α subunit bind the insulin and β subunit span the membrane. It has got
intrinsic tyrosine kinase activity .

• Hormones can be classified according to:

– Chemical composition
– Solubility properties
– Location of receptors
– Nature of signal used to mediate hormonal action within the cell
.
 Steps involved
• General steps involved in producing a coordinated responses
to a particular stimulus are:-
– Recognition
• of stimulus
– Hormone release
• Group 1 and II
– Signal generation
• Group I – hormone-receptor complex
• Group II- many different signal
– Effects
• Group I- Gene transcription
• Group II- gene transcription, channels and transporters, protein
translocation, protein modification
 Signal Transduction
• Defined as the ability of a cell to change behaviour in response to
a receptor-ligand interaction
• As the result of binding the receptor, other molecules or second
messengers are produced
• Signal transduction pathway can act to amplify the cellular
response to an external signal.
• Messenger molecules may be amino acids, peptides, fatty acids
and lipids.
• Hydrophilic messengers bind to cell membrane receptors
• Hydrophobic messengers bind to intracellular receptors which
regulates expression of specific genes
 Signal generation
• Autocrine signaling
– a form of cell signaling in which cell secretes a hormone or chemical
messenger that bind to autocrine receptors on the same cell

• Endocrine signaling
– Endocrine cells release hormones that act on distant target cells in the body.
Can be distinguished from 2 types of signaling: neural & paracrine signaling

• Synaptic signaling
– Similar to paracrine signaling but there is a special structure called the
synapse between the cell originating and the cell receiving the signal.
– Only occurs between cells with the synapse. Eg. Neuron and muscle

• Paracrine signaling
– a form of cell-cell communication in which a cell produces a signal to induce
changes in nearby cells
GROUP I HORMONES:
• Group I hormones are lipophilic.
• They diffuse through the plasma membrane of all cells and they
encounter their receptor receptors intracellularly.
• These receptors can be
located in the cytoplasm
or in the nucleus of target
cells.
• Example:
– Glucocorticoids
GROUP II HORMONES- cAMP Intracellular
Signal

• cAMP was the first signal that was identified

in mammalian cells.
• Different peptide hormones can either
stimulate or inhibit the production of cAMP
from adenylyl cyclase.
Cyclic AMP system

Receptor

G-protein
Stimulate (Gs) and
inhibit (Gi)
Adenylate cyclase

c-AMP

Protein kinases
 1 2 Nitric 3 4 5
oxide
T-cell
Glucagon Insulin
Activation

1 2 3 4 5
G G G IP3 G
G protein Tyrosine

Cyclic AMP Cyclic GMP Ca2+ Diacylgycerol Protein kinase

substrates

PK-A PK-G Calmodulin PK-C

Protein Ser/Thr
kinases
Protein substrates
Multifunctional Protein substrates
kinases
End result is Other
phosphorylation of phospholipases
one or more proteins Protein substrates
 G-Protein Coupled Receptors
• Many of the group II hormones bind to receptors that
couple to effectors through a GTP- binding protein
intermediary.

• These receptors have seven membrane spanning domains.

• Members of this class which signal through G- proteins are

called, G-protein-coupled receptors.

• It is the largest family of cell surface receptors.

How G-protein
is activated
 hormone Inhibitor

RS Ri

GDP 
AC
GTP
  GDP

GTP 4 ATP

AT P
Inactive
Protein protein
4 cAMP kinase

Adenylate cyclase ADP

Active
Signaling System protein

Cell response
 When G-protein signaling is
disrupted
• G-protein-related diseases are characterized by either
deficient or excessive G-protein signal transmission.
• Decrease in the production of G-protein
– Night blindness
• mutations in G(t) protein alpha-subunit

– Pseudohypoparathyroidism
• genetic loss of G(s) protein alpha subunit result in non-
responsive to parathyroid hormone

– Whooping cough
• Increase in the production of G-protein can arise
through increased signal initiation or defective signal
termination
– Testotoxicosis-
• mutation in the receptor for luteinizing hormone that over-
stimulate G(s) proteins- result in the excessive production of
testosterone

– Vibrio Cholera-
• symptoms which result from the action of a bacterial toxin that
adds ADP-ribose to G(s) protein alpha-subunits to prolong
their activation leading to fatal diarrhoea
 Protein kinase A
• PKA is a heterotetrameric molecule and consists of
two regulatory subunits and two catalytic subunits.

• 4cAMP+ R2C2↔ R2.(4cAMP)+ 2C

• R2C2 is not active catalytically, but the C unit is

active.

• The active C unit catalyzes the transfer of γ phosphate

of ATP to a serine or threonine residue in a variety of
proteins.
• Phosphatase remove this phosphate and terminate the
physiologic responses

• Phosphodiesterase can be also terminate this action

by converting cAMP to 5’AMP

• Inhibitors of phosphodiesterase like caffeine, which is

a methylated xanthine derivative, increase the
concentration of cAMP and prolongs the action of
hormones
 cGMP intracellular signal

• cGMP is made from GTP by the enzyme

gaunylylcyclase
• Atrial natriuretic peptide and nitric oxide function
through this signal
• These are potent vasodilators
• Inhibitors of cGMP phosphodiestrase is sildenafil
(Viagra)
 Reminder
• Most hormones never penetrate cells
• All hormones have receptors
• Internal responses are initiated by the receptor
• Receptors work with G proteins
• G proteins stimulate protein kinases
• Protein kinases comprise a cell signaling
cascade
• G proteins turn off when GTP is hydrolyzed to
GDP, canceling the hormone action