III. Chemical Characteristics and Synthesis of Bioregulators

• Amino acids, amines, peptides and proteins

• Steroid Bioregulators

• Thyroid hormones

• Eicosanoids

• Other important regulators

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: -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 CatecholaminesEnzymes involved:• Tyrosine hydorxylase• Dopa decarboxylase• Dopamine hydroxylase• Phenylethnolamine- N-

CH3–transferase (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

Metabolism of Norepinephrine in the Central Nervous System

• Release of catecholamine neurotransmitters is metabolised by:

MAO = monoamine oxidase

COMT = catechol-O-methyl transferase

[II] Indolamines and Melatonin

Serotonin: 5’hyroxytrypamine

NAT: N-acethltransferase

HIOMT: Hydroxyindole-O-methyltransferase

Melatonine: N-acetyl-5-methoxytryptamine

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

Serving as neurotransmitter

L-aromatic amino acid decarboxylase

[III] Steroid Bioregulators

The Steroid Nucleus

Steroid nucleus

Naturally Occurring Steroids

Estrogens and Androgens

Some Synthetic Steroids and Nonsteroids

Isolated from plant, with estrogenic activity Synthetic estrogenic compound

A potent synthetic glucocorticoid hormone Antagonist of estrogen receptor

Corticosteroids Progestens

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: 17-hydroxylase, 17,20-Lyase CYP19: Aromatase CYP11B1: 11-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

[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, TR-1 and TR-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

Ecdysone

Juvenile Hormone

[V] Insect Developmental Hormones

-ecdysone

-ecdysone: 20- hydroxy-ecdysone

JH-IJH-IIJH-III

[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

• PGF2 functions as uterine leuteolytic substance in certain mammals

[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

Prostaglandin Structures

Biosynthesis of

Eicosanoids

[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

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

• 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

MSH-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??

[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 -interferon which can transform macrophage to attach viral infected cells. Interleukin, -interferon and cytokines are involved in immune responses

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

Reading Assignment (III)

1. Melatonin2. Serotonin3. Tamoxifen4. Eicosanoid5. C-peptide of pro-insulin6. Processing in vitro of placental peptide hormone by

smoth microsome 7. Nobel Lecture by Sune Bergstrom