Transcript III-Chemical Characteristics and Synthesis of Bioregulators

III. Chemical Characteristics and
Synthesis of Bioregulators
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Amino acids, amines, peptides and proteins
Steroid Bioregulators
Thyroid hormones
Eicosanoids
Other important regulators
Chemical Nature of Hormones
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Peptide and protein hormones (most abundant): thyrotropin
releasing hormone (TRH), gonadotropin releasing hormone
(GnRH), growth hormone (GH), prolactin (PRL), insulin, insulinlike growth factor-I (IGF-I) etc.
Amino acid derivatives: thyroid hormone, epinephrine etc.
Steroid hormones: testosterone, estrogen & cortisone etc.
Lipids: prostaglandin, retinoic acid etc.
Nucleotides: cAMP, cytokinins, cGMP etc.
Oligosaccharides: a-1,4-oligogalacturonides (OGs)
Gases: CO, ethylene etc.
Ecosanoids: Derived from arachidonic acid; e.g., prostaglandins,
leukotrienes (produced by leukocyte to cause inflammation in
asthma) and thromboxanes (It acts in the formation of blood clots
and reduce blood flow to the site of a clot)
[I] Catecholamines
When an amine group is attached to a catechol,
it is termed as a catecholamine
catechol
Examples of catecholamines are: Dopamine,
epinephrine and norepinephrine
Catecholamines are synthesized from tyrosine by
neurons and cells of the adrenal medulla
Biosynthesis of Catecholamines
Enzymes involved:
• Tyrosine hydorxylase
• Dopa decarboxylase
Dopamine b hydroxylase
Phenylethnolamine- NCH3–transferase (PNMT)
• Tyrosine hydroxylase
immunoreactivity is
frequently used as a
biochemical marker to
locate catecholaminesecreting cells
• Catecholamines are more
than just
neurotransmitters, DA,
NE and E can also be
released into the
circulation to function as
hormones
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Metabolism of Norepinephrine in the
Central Nervous System
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Release of
catecholamine
neurotransmitters
is metabolised by:
 MAO =
monoamine
oxidase
 COMT =
catechol-Omethyl
transferase
[II] Indolamines and Melatonin
Serotonin:
5’hyroxytrypamine
L-aromatic amino
acid decarboxylase
NAT: Nacethltransferase
Serving as
neurotransmitter
HIOMT:
Hydroxyindole-Omethyltransferase
Melatonine: Nacetyl-5methoxytryptamine
Melatonine is secreted from pineal gland primarily in the dark phase which is
important in regulating cyclic functions and having negative inferences on
thyroid and reproductive functions. Reading Assignment: Melatonin
[III] Steroid Bioregulators
Steroid nucleus
The Steroid Nucleus
Naturally Occurring Steroids
Estrogens and Androgens
Some Synthetic Steroids and Nonsteroids
Isolated from plant, with estrogenic activity
A potent synthetic glucocorticoid hormone
Synthetic estrogenic compound
Antagonist of estrogen
receptor
Corticosteroids
Progestens
Enzymes Involved in Steroid Synthesis
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All vertebrate steroid bioregulators are synthesized
from cholesterol which is synthesized from acetyl CoA
Steroidogenesis: synthesis of steroid nucleus from
acetyl CoA
Key enzymes involved in synthesis of steroid
bioregulators are:
• CYP21: C24 hydrolase
 CYP11A: Cholestrol side chain cleavage (20-22 Desmolase)
 CYP17: 17a-hydroxylase, 17,20-Lyase
 CYP19: Aromatase
 CYP11B1: 11b-hydroxylase
 CYP11B2: Alderstrone synthetase
 CYP1A1: Aryl hydrocarbon hydroxylase
• Steroid bioregulators in the circulation are bound to
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plasma binding proteins
Reading Assignment: Sex Hormone Binding Globulin
[IV] Thyroid Hormones
• T3 and T4 are synthesized
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T3 or T4 are bound to plasma proteins in the
circulation
from tyrosine
Most thyroid hormones are
bound to plasma proteins
Receptor molecules for T3
and/or T4 are nuclear
receptors, two major isoforms,
TRy-1 and TRb-1
Tyrosine is first incorporated
into a globular protein
(thyroglobulin) and then
iodinated by thyroid
peroxidase to form DIT
Two DITs are to form T4
Through deiodination at the
outer ring, T3 is formed
T4 or T3 moieties are
hydrolyzed from thyroglobulin
and released into the
circulation
[V] Insect Developmental Hormones
a-ecdysone
b-ecdysone: 20hydroxy-ecdysone
Ecdysone
JH-I
JH-II
JH-III
Juvenile Hormone
[VI] Eicosanoids (I)
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Eicosanoids are small lipids derived from a common precursor,
arachidomic acid
Eicosanoids include: prostaglandins, leukotrienes and
throboxanes
Prostaglandin was discovered by Maurice Goldblatt of England
and U.S. Von Euler of Sweden. By elucidating the biological
importance and the biosynthetic pathway of prostaglandin, Sune
Bergstrom, Bengt Samuellson and John Vane were awarded with
Nobel Prize in Physiology and Medicine in 1982
Postaglandins were first found in prostate gland, and
subsequently found in many tissues of men and women
Prostaglandins exhibit diverse actions: stimulation of smooth
muscle contraction in intestine and uterus, vasodilatation , and
modulation of central nervous system function
Prostaglandins also stimulate synthesis of corticosteroids,
testosterone and a variety of enzymes
PGF2a functions as uterine leuteolytic substance in certain
mammals
[VI] Eicosanoids (II)
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Prostaglandins also reduce progesterone synthesis by the
corpus luteun, induce ovulation and lactation in rodents, and
may be involved in induction of labor
Prostaglandins may induce inflammation and fever
Prostacyclin (PGI2) , another form of prostaglandin, is a potent
inhibitor of blood platelet aggregation and inhibits blood clotting
Thromboxanes A2 causes translocation of free calcium ions to
bring about changes associated with the shape of blood
platelets to facilitate blood clotting
Leukotrines are synthesized and released by white blood cells in
response to injury. They contribute to inflammation or allergic
responses by causing contraction of vascular smooth muscle
and by increasing vascular permeability. Increasing levels of
leukotrines have been associated with allergic reactions,
asthma, cystic fibrosis, septic shock and a number of other
disorders
Prostaglandin Structures
Biosynthesis
of
Eicosanoids
[VI] Peptide and Protein Bioregulators
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Peptide or protein bioregulator are
encoded by genes
The mRNAs of peptide or protein
bioregulators are translated on the
endoplasmic reticulum membrane
which as recognized by signal
recognition particle and docking protein,
and direct the pre-pro-peptide into the
cisternae of the endocriplasmic
reticulum
The signal peptide and the pro
sequence are removed by proteolytic
cleavage and the mature peptide is
secreted out of the cell
For other bioregulators that contain
carbohydrates and/or lipids (e.g., GTHs
or TSH), acetyl group or amide group,
these components are added to the
mature protein while is in the cisternae
of the smooth endoplasmic reticulum or
Golge Complex
Translation of Peptide or Protein Bioregulators
Post translational Processing of Proteins
Reading Assignment:
Processing in vitro of placental peptide hormone by smooth microsome
Structures of Insulin Family Proteins
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This slide shows the
structural homology
among insulin family
proteins
Insulin family
proteins: insulin,
insulin-like growth
factor-I, insulin-like
growth factor-II and
relaxin
Primary
Structures of
Several
Prohormones
gMSH-CLIP = adrenalcorticotropin (ACTH)
Somatostatin-28 more
potent than Somatostatin-14
Neurophysin serve as a
binding protein for the
transport of ADH
(vasopressin )
**Important Question
Are the pro-hormone
sequence biological
active??
[VII] Other Important Bioregulators
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Acetylcholine (Ach):
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Serves as a major neurotransmitter in the peripheral nervous system
and in the brain
It is synthesized from choline and acetate by choline acetyltraansferase in the membrane of the postsynaptic cells
It functions by first binding to the acetylcholine receptor
Gamma-Aminobutyric Acid (GABA):
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It functions as an inhibitory neurotransmitter
It is formed mainly from glutamate by glutamate decarboxylase
Interleukins:
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Interleukins are secreted by lymphocytes and macrophages
Interleukins function in autocrine/paracrine fashion within the vascular
system and several lymphatic tissues.
There are more than a dozen recognized interleukins. IL-1 can activate
helper T-cell; IL-2, a mitogen secreted by helper T-cell which can
stimulate B-cell to divide and form plasma cells, it also stimulate
helper T-cells to proliferate; IL-6 is known to interact with adrenal cells
to release cortisol
Helper T-cells also produce g-interferon which can transform
macrophage to attach viral infected cells. Interleukin, g-interferon and
cytokines are involved in immune responses
Other Important Bioregulators (II)
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Retinoic acid is a metabolite of vitamin A (retinol)
It mediates the functions of vitamin A required for growth and
development in chordate animals including all higher animals
from fishes to humans
During early embryonic development, retinoic acid acts
through Hox genes to determine the anterior/posterior axis of
the animal
Reading Assignment (III)
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Melatonin
Serotonin
Tamoxifen
Eicosanoid
C-peptide of pro-insulin
Processing in vitro of placental peptide hormone by
smoth microsome
7. Nobel Lecture by Sune Bergstrom