BIOCHEMICAL ASPECT OF HORMONE

AND SIGNAL TRANSDUCTION

Department of Biochemistry
Objectives

Definition of hormone

Hormone affect homeostasis and its mechanism

Classification of hormone : distance of action, chemical structure, water solubility

Mechanism of action of hormones

Differences between lipophilic and hydrophilic hormones

Intracellular signal transduction pathway and second messengers activated by hormones

Pharmaceutical applications of hormones and their signal transduction pathways

 Signalling molecules
• The cells of an organism are constantly receiving
information about their surrounding environment
in order to control and regulate their activities.
• Cells also need to communicate to other cells to
ensure the control and regulation of systems
within the organism.
• Molecules that enable cells to receive
information and communicate with other cells
are called signalling molecules or ligands.
 Receptors
• For a cell to act on and respond to a chemical
signal the cell must have a receptor to receive
the signal.
• Once the signalling molecule has interacted with
the receptor, the information needs to be
processed to produce the appropriate cellular
response.
• Signal processing within a cell may involve a
series of molecular steps called a signal
transduction pathway.
Types of signals
 Types of signals
• There is constant ‘chemical chatter’ between
cells in multicellular organisms.
• Chemical signals can be classified according to
the distance the signal needs to travel:
– Autocrine signals – a cell secretes signalling molecules
that can bind to its own receptors.
– Paracrine signals – signals are released by cells into
the extracellular medium in their neighborhood and
act locally
– Endocrine signals – signals produced in endocrine
glands are secreted into the bloodstream and can be
distributed throughout the body
 Donald V. and Judith V “Biochemistry” second edition John Wiley&Sons. Inc, 1995 p.1261
Guyton & Hall “Medical Physiology” Introduction to Endocrinology. Tenth edition, Saunder, 2000, p. 836-845
 What are hormones?
Hormones : Biochemical compounds excrete from cells
and pass through extracellular fluid or blood circulation to act
at the other cells.

Properties of Hormones
- Release in response to appropriate stimuli
- Little amount in the body : uM, pM, fM
- Specific receptors on specific types of cells
- Amplified effects by target cells
- Actions depend on many factors
- Control by feedback inhibition

Function of Hormones : Keep body homeostasis

 Signalling by hormones
• Lipid-soluble hormones pass
through the cell membrane and bind
to receptors in the cytosol.
• Water-soluble hormones bind to
receptors in the cell membrane
and stimulate second messenger
systems.
• In both cases, the signals received
by the cells go through a cascade
of changes, called signal
transduction, and finally the cell
initiates its response.
Types of chemical mediators
depend on chemical structure : 4 classes
1. Peptide or proteins ex. hormones from pituitary gland,
parathyroid gland, uterus, kidney, GI-tract, brain, heart, thymus
(insulin, glucagon, etc.)
2. Derivatives of amino acids ex. Catecholamines (epinephrine,
norepinephrine), thyroxine (T4), triiodotyronine (T3), melatonin
3. Steroids ex. aldosterone, cortisol, testosterone, estradiol,
progesterone
4. Derivatives of fatty acids ex. prostaglandins,
thromboxane
Peptide hormone synthesis :
preprohormone  prohormone  active hormone

Active insulin
Derivative of amino acids

• Tyrosine is an amino acid which is present in protein in the

diet and is used as a supplement for Parkinson's disease,
phenylketonuria, and to improve memory
• Levodopa (Bendopa(R), Sinemet(R)) for treatment of Parkinson
disease
Steroid :
precursor of steroid hormone synthesis is cholesterol

3 cyclohexyl rings + 1 cyclopentyl ring

Derivative of fatty acids
(eicosaniod)
Eicosanoid is used as a collective name for molecules derived from 20-
carbon fatty acids (arachidonic acids). Current usage limits this to the
leukotrienes and prostanoids (prostaglandins, thromboxanes)
Types of hormones depend on water
solubility : consist of 2 classes
Hydrophilic hormones Hydrophobic hormones
Lipophilic hormones

1. Peptide or proteins 1. Steroids

2. Derivatives of amino 2. Derivatives of fatty acids
acids (except thyroid
hormones)
Processes of action of hormone
1. Synthesis from specific cells
hydrophilic hormones are synthesized and kept in the
intracellular vesicle
lipophilic hormones are synthesized only when there is the
specific stimulation

2. Secretion and transport

protein carrier : albumin

3. Action at target cells

4. Biological responses
Hormonal involvement in
response to a stimulus
Recognition STIMULUS

Gr. I hormones Gr. II hormones

Hormone release (steroids)
(intracellular Rp.)
(peptides/proteins/dev. fatty acid)
(membrane Rp.)

Signal generation Hormone-Rp complex Many different signals

Gene Transporters Protein Protein

Effects transcription Channels translocation modification

Coordinated response to stimulus

Harper’s Illustrated Biochemistry, 21th ed, 2003

Mechanism of action of
Lipophilic hormones
Hormone responsive element (HRE)
• glucocorticoid responsive element (GRE)
• estrogen responsive element (ERE)
• thyroid hormone responsive element (TRE)
etc.

• Transcription = process of mRNA

synthesis from DNA
• Translation = process of protein
synthesis

Transcription Translation

Animation of steroid hormone action

Animation of thyroxine action
Processes of action of
Hydrophilic hormones
PEPTIDES/PROTEINS

Membrane receptor

Intracellular messengers

Intracellular signal transduction

pathway
(signal transduction cascade)
Signal transduction pathway
- any process by which a cell converts one kind of
signal or stimulus into another
Hormone
- processes referred to as signal transduction often
Receptor involve a sequence of biochemical reactions inside
the cell, which are carried out by enzymes and
linked through second messengers
- take place in as little time as a millisecond or as
long as a few seconds.
- In many transduction processes, an increasing
number of enzymes and other molecules become
engaged in the events that proceed from the initial
stimulus. In such cases the chain of steps is
referred to as a "signaling cascade" or a "second
messenger pathway“
- results in a small stimulus eliciting a large response

http://en.wikipedia.org/wiki/Signal_transduction
Facts on membrane receptors
Specific membrane receptors on specific cell types respond to
specific hormones
Three classes of membrane receptors
(only 2 of 3 are focused)
1. Neurotransmitter receptors linked to ion channels
ex. Cholinergic nicotinic receptors, GABA receptors
2. Catalytic receptors (Rp tyrosine kinase, RTKs)
ex. insulin, mitogen (epidermal growth factor: EGF, platelet-derived growth
factor: PDGF)
3. Receptors involving second messenger
(G-protein coupled Rp, GPCRs)
consists of 2 types
3.1 Receptors couple to adenylate cyclase
ex. glucagon, epinephrine (β)
3.2 Receptors couple to phosphatidylinositol hydrolysis
ex. epinephrine ()
Structure of RTK and GPCR
RTK RTK GPCR

3 parts of membrane receptors

1. extracellular part: binds with hormones
2. transmembranous part: holds with membrane
3. cytoplasmic part: transduces external stimuli
into the cell and activates second messengers
 Insulin signaling pathway
Tyrosine kinase

RTK

autophosphorylation Y = tyrosine

Insulin responsive substrate phosphorylation

PKB
SGK p70S6K
aPKC
PDGF pathway : tyrosine kinase
Function of protein kinase (phosphorylation)
• promotes a conformational change of enzymes

• rather than tyrosine, threonine and serine are the targets of

phosphorylation
Tyrosine kinase inhibitors
• Imatinib mesylate (PDGF-specific) : also known as Gleevec® (USA),
Glivec® (Europe), STI 571, or CGP57148
• competitively inhibiting phosphorylation of downstream effector

• Gefitinib (EGF-specific) : Iressa®

• inhibit autophosphorylation of the receptors

http://arjournals.annualreviews.org/doi/full/10.1146/annurev.pharmtox.45.120403.100124?cookieSet=1
NF-B signaling pathway

• Glucocorticoids inhibit the NF- B pathway:

- increase IB mRNA
- glucocorticoid Rp competes with NF B for binding to
coactivator
- glucocorticoid Rp directly binds to p65

• Prednisolone relieves inflammation

Harper’s Illustrated Biochemistry, 25th ed, 2005

GPCR
• GPCRs are implicated in a number of
diseases

G-protein
Receptors couple to adenylate
cyclase

cAMP dependent protein kinase

(protein kinase A, PKA)

animation
In muscle, In fat cell
liver

Effects of
glucagon/epinephrine to
increase blood glucose
level

Animation of epine
phrine action
Receptors couple to guanylyl
cyclase cGMP
GTP

• Stimulators : nitropusside, nitric oxide, sodium

azide etc.
• Efffects : smooth muscle relaxation, vasodilatation
• Drug : Viagra (inhibitors of cGMP
phosphodiesterase)

Activate guanylyl cyclase

Receptors couple to
phosphatidylinositol hydrolysis
Stimulators: acetylcholine, antidiuretic hormone, α1-type catecholamines


Amplifier in phophatidylinositol
hydrolysis pathway

• Calcium in ER is
released to cytosol.
• It binds to calmodulin
or may help to activate
PKC.
Epinephrine actions via
phosphatidylinositol
hydrolysis
Second messengers of membrane
receptor pathway

• cAMP
• cGMP
• calcium
• IP3
• DAG
Second
messengers
Second messenger systems
• Receptors associated with second messenger
systems include G protein-coupled receptors,
tyrosine-kinase receptors, and ion-channel
receptors.
• The ligand binds to a receptor on the cell's
plasma membrane activating an associated
molecule (the second messenger).
• The second messenger activates other
intracellular molecules that elicit a response.
Second messenger systems
 Neurotransmittors
• A nerve ending in the region of a synapse with another cell, contains
numerous mitochondria and many tiny vesicles containing
neurotransmitter molecules.
• When an action potential enters the nerve ending, the vesicles move to
the cell membranes and release their contents into the synaptic gap.
• These molecules diffuse across the gap to interact with specific
receptors on the postsynaptic cell membrane.
 Neurotransmitters
• Neurotransmitters cannot
pass through the plasma
membrane.
• They interact with a
receptor on the cell
surface which opens a
protein channel and allows
Na+ (sodium ions) to enter
the cell and change the
membrane potential
(important for
electrochemical potential).
 Signal Transduction
• Signal transduction refers to the way that receptors on the
cell surface convert incoming signals into information leading
to an appropriately coordinated response.
• The binding of a signalling molecule with it specific receptor
initiates a cellular response.
• Like homeostasis, the action of signalling molecules can be
understood in terms of the stimulus response model.
• The binding of the signalling molecule to the receptor
affects cellular chemicals.
• Changes in chemical activity in a cell cause changes in
function.
 SIGNAL

SIGNAL
TRANSDUCTION

APOTOSIS

GROWTH SURVIVAL PROLIFERATION

DIFFERENTIATION

MIGRATION
Signal transduction cascades
are the nervous system of
the cell
The basics of signal transduction
• Signal is received.
• Signal is amplified.
• Response is usually a change in
protein levels or associations.
• Specificity possible at all
levels.
• Feedback possible.
• Conservation between many
organisms . . . and pathways
 Signal transduction amplifies the original
signal
• The below-surface receptors activated by steroids and the G or
other proteins activated as a result of water-soluble hormones both
trigger a cascade of events.
• These events generally involve proteins and ultimately lead to a
biological response within the cell relevant to the original
hormone signal.
• This process in which a cell converts one kind of signal into another,
by a series of relay molecules and other proteins, is called signal
transduction.
• Within a cell, signal transduction amplifies the signal that the
original hormone molecule brought to the cell.
• A signal brought by a single hormone molecule or a few hormone
molecules can be amplified through many steps to induce reactions
that involve many substrates.
• Binding of antigen to
a B cell receptor
transduces a signal
which upregulates
transcription of genes
important in
proliferation of B
cells.

• It can be seen that

transduction of the
signal is a non-linear
process.
 IMPORTANT CONCEPT:
Signaling is nonlinear! Think of signal transduction as a
web not a line . . .
 Responses to Signals
• Activation of genetic material, DNA.
• May lead to the production of proteins, including
enzymes.
• Enzymes become involved in a range of metabolic
reactions within the cell.
• Response may be the production of another hormone
that will leave the cell and carry different kinds of
signals to other cells.
• Alternatively signals may suppress the production of
proteins, including enzymes and therefore down-regulate
particular metabolic reactions within the cell.
 Apoptosis
• Apoptosis occurs in response to particular cell signals.
• Also known as programmed cell death (PCD), apoptosis is a normal part of the
life of cells.
• Cell death is important for:
– Developmental changes in growing embryos
– Ridding tissues of old, infected or damaged cells
– Removing immune cells which attack “self”
– Removing cells which have sustained DNA damage so that they do not continue to
reproduce and form cancers

• Too little apoptosis can lead to cancer and too much can cause degenerative
diseases such as Alzheimer disease.

• Cell death occurs when the cell membrane shrinks, DNA fragments and lysosomes
empty their contents into the cell causing the cellular components to be broken
down. The dead cell is then consumed by phagocytes.
Summary 1
- Three chemical mediators : endocrine, paracrine and autocrine

- Chemical mediators can be divided into 4 classes upon their structures

- Peptide/protein and derivative of amino acids are hydrophobic whereas

steroid and derivative of fatty acids are lipophilic

- Steroid and peptide/protein hormones act on cell with different

mechanisms
Summary 2
Intracellular Membrane receptor
receptor
• steroid hormones, sex hormones, • peptide hormones ex. glucagon,
thyroid hormones insulin, epinephrine
• Water/lipid soluble
• lipid soluble (peptide/protein, dev.fatty
(steroids, thyroid hormones) acid)
• regulate gene expression • trigger transmembrane signals
(transcription)
• • onset of action : immediately
onset of action : hour (s) to day
• effect may persists for a time
• effect not persist
Summary 3
- Intracellular receptors of steroid hormones are different among hormones

- Two main types of membranous receptors : RTK and GPCR

- RTK and GPCR activate intracellular signal transduction pathway (signal

cascade) by phosphorylation and causes protein modification/translocation
and gene transcription.

- Abnormalities of signal cascade cause diseases : cancers

- Inhibitors of abnormal signal cascade are important drugs

: RTK pathway: Imatinib in CML
: NF kB pathway: Prednisolone in inflammation relieve
: GPCR pathway: Viagra® in impotence
References
1. Guyton & Hall “Medical Physiology” Introduction to
Endocrinology. Tenth edition, Saunder, 2000, p. 836-845
2. Donald V. and Judith V “Biochemistry” second edition
John Wiley&Sons. Inc, 1995 p.1261
3. Harper’s Illustrated Biochemistry, 25th ed, 2005
4. http://en.wikipedia.org/wiki/Signal_transduction
5. Other related websites
6. http://biochem.md.kku.ac.th