III. Chemical Characteristics and Synthesis of Bioregulators

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III. Chemical Characteristics and Synthesis of
Bioregulators

• Amino acids, amines, peptides and proteins
• Steroid Bioregulators
• Thyroid hormones
• Eicosanoids
• Other important regulators

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Chemical Nature of Hormones

• Peptide and protein hormones (most abundant)
  thyrotropin releasing hormone (TRH), gonadotropin
  releasing hormone (GnRH), growth hormone (GH),
  prolactin (PRL), insulin, insulin-like 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)

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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
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Biosynthesis of Catecholamines

• Enzymes involved
• Tyrosine hydorxylase
• Dopa decarboxylase
• Dopamine b hydroxylase
• Phenylethnolamine- N-CH3transferase (PNMT)
• Tyrosine hydroxylase immunoreactivity is
  frequently used as a biochemical marker to locate
  catecholamine-secreting 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

• Release of catecholamine neurotransmitters is
  metabolised by
• MAO monoamine oxidase
• COMT catechol-O-methyl transferase

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II Indolamines and Melatonin
Serotonin 5hyroxytrypamine NAT
N-acethltransferase HIOMT Hydroxyindole-O-methyl
transferase Melatonine N-acetyl-5-methoxytryptam
ine
L-aromatic amino acid decarboxylase
Serving as neurotransmitter
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
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III Steroid Bioregulators
Steroid nucleus
The Steroid Nucleus
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Naturally Occurring Steroids
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Estrogens and Androgens
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Some Synthetic Steroids and Nonsteroids
Isolated from plant, with estrogenic activity
Synthetic estrogenic compound
A potent synthetic glucocorticoid hormone
Antagonist of estrogen receptor
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Corticosteroids
Progestens
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Enzymes Involved in Steroid Synthesis

• 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 plasma binding proteins
• Reading Assignment Sex Hormone Binding Globulin

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IV Thyroid Hormones

• T3 and T4 are synthesized 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

T3 or T4 are bound to plasma proteins in the
circulation
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V Insect Developmental Hormones
a-ecdysone
b-ecdysone 20- hydroxy-ecdysone
Ecdysone
JH-I JH-II JH-III
Juvenile Hormone
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VI Eicosanoids (I)

• 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

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VI Eicosanoids (II)

• 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

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Prostaglandin Structures
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Biosynthesis of Eicosanoids
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VI Peptide and Protein Bioregulators

• 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

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Translation of Peptide or Protein Bioregulators
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Post translational Processing of Proteins
Reading Assignment Processing in vitro of
placental peptide hormone by smooth microsome
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Structures of Insulin Family Proteins

• 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

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Primary Structures of Several Prohormones
gMSH-CLIP adrenalcor-ticotropin
(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??
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VII Other Important Bioregulators

• Acetylcholine (Ach)
• Serves as a major neurotransmitter in the
  peripheral nervous system and in the brain
• It is synthesized from choline and acetate by
  choline acetyl-traansferase in the membrane of
  the postsynaptic cells
• It functions by first binding to the
  acetylcholine receptor
• Gamma-Aminobutyric Acid (GABA)
• It functions as an inhibitory neurotransmitter
• It is formed mainly from glutamate by glutamate
  decarboxylase
• Interleukins
• 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

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Other Important Bioregulators (II)

• 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

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Reading Assignment (III)

• Melatonin
• Serotonin
• Tamoxifen
• Eicosanoid
• 5. C-peptide of pro-insulin
• 6. Processing in vitro of placental peptide
  hormone by smoth microsome
• 7. Nobel Lecture by Sune Bergstrom