bioch

• The Endocrine System


  A system of the body which consists of ductless glands that release HORMONES into the blood streams
• The Endocrine System


  • Interacts closely with the nervous system
• Endocrine Organs


  • Pituitary gland
  • Pineal gland
  • Thyroid gland
  • Parathyroid gland
  • Adrenal gland
  • Pancreas
  • Thymus
  • Gonads
  • Hypothalamus
• Hormones


  A substance that is synthesized in one organ and transported by the circulatory system to act on another tissue
• Hormones


  They can also act on adjacent cells (paracrine action) and on the cell in which they were synthesized (autocrine action) without entering the systemic circulation
• The Target Cell Concept


  • Hormones affected a single cell type – or only a few kinds of cells – and that a hormone elicited a unique biochemical or physiologic action
  • A given hormone can affect several different cell types
  • More than one hormone can affect a given cell type
  • Hormones can exert many different effects in one cell or in different cells
• Hormone Receptors

  • Receptors discriminate precisely - they must distinguish not only between different hormones present in small amounts but also between a given hormone and the 10^6 – to 10^9 – fold excess of other similar molecules
• Receptor Specificity and Selectivity


  Defined by its ability to selectively bind a given hormone to its cognate receptor
• Receptor Binding


  • Binding should be SPECIFIC, i.e, displaceable by agonist or antagonist
  • Binding should be SATURABLE
  • Binding should OCCUR WITHIN THE CONCENTRATION RANGE of the expected biologic response
• Functional Domains of Receptors

  • Recognition Domain - Binds the hormone ligand
  • Coupling Domain - Generates a signal that couples hormone recognition to some intracellular functions
• Coupling of Hormone Binding to Signal Transduction

  1. Steroid, retinoid, and thyroid hormones interact with INTRACELLULAR RECEPTORS (Ligand – receptor complex) provides the signals to specific genes affects rate of transcription

  2. Polypeptide and protein hormones, and the catecholamines bind to receptors located in the PLASMA MEMBRANE generate a signal that regulates various intracellular functions (ie changing the activity of enzyme)
• Functional Domains of Steroid, Thyroid, and Retinoid Hormone Receptors

  • Binds the hormone
  • Binds to specific DNA regions
  • Involves in the interaction with other coregulator proteins that result in the activation (or repression) of gene transcription
  • Specifies binding to one or more other proteins that influence the intracellular trafficking of the receptor
• Receptor-Effector Coupling


  • Provides the FIRST STEP in amplification of the hormonal response
  • Differs from plasma carrier proteins (bind hormone but do not generate a signal)
• Classification of Hormones

  • Chemical composition
  • Nature of the signal used to mediate hormonal action within the cell
  • Solubility properties
  • Location of receptors
• Hormones and Their Derivatives


  • Cholesterol - Synthesized in final form and secreted immediately
  • Catecholamines - Synthesized in final form and stored in the producing cells
  • Insulin - Synthesized from precursor molecules in the producing cell, processed and secreted upon a physiologic cue
  • T3 and DHT - Converted to active forms from precursor molecules in the periphery
• Adrenal Steroidogenesis


  1. Synthesized from cholesterol

  2. Mostly derived from the plasma, small portion is synthesized in situ from acetyl-CoA via mevalonate and squalene

  3. Esterified and stored in cytoplasmic lipid droplets

  4. Requires ACTH-dependent steroidogenic acute regulatory (StAR) protein for the transport of cholesterol to P450scc in the inner mitochondrial membrane
• Adrenal Steroidogenesis


  • Mineralocorticoid Synthesis - 11-Deoxycorticosterone (DOC), Corticosterone, Aldosterone
  • Glucocorticoid Synthesis - Cortisol
  • Androgen Synthesis - Dehydroepiandrosterone (DHEA), Androstenedione, Testosterone
• Testicular Steroidogenesis

  1. Cholesterol - immediate precursor of the gonadal steroids

  2. Rate Limiting Steps: Delivery of cholesterol to the inner membrane of the mitochondria by the transport protein StAR, 5 enzyme activities contained in 3 proteins - 3β-hydroxysteroid dehydrogenase (3β-OHSD) and Δ5,4- isomerase, 17α-hydroxylase and 17,20-lyase, 17β-hydroxysteroid dehydrogenase (17β-OHSD)
• Testosterone Metabolism Pathways


  • Oxidation at the 17 position - 17-ketosteroid (less active or generally inactive)
  • Reduction of the A ring double bond and the 3-ketone - DHT (potent active form)
• Dihydrotestosterone (DHT)


  • Most significant product of testosterone
  • Active form found in prostate, external genitalia, some areas of the skin
  • Plasma content in adult male is about 1/10 that of testosterone, ~400 μg is produced daily (vs 5mg of testosterone), 50 to 100μg are secreted by testes
• Ovarian Steroidogenesis


  1. 17β-Estradiol - primary estrogen of ovarian origin

  2. Estrone - synthesized in numerous tissue (more abundant), major source of estrogens in postmenopausal women

  3. Estriol - produced during pregnancy, comes from placenta

  4. Theca Cells - source of androstenedione and testosterone, converted by the aromatase enzyme in granulosa cells to estrone and estradiol, respectively

  5. Progesterone - produced and secreted by the corpus luteum as an end-product hormone
• Aromatase


  • Increased activity may contribute to "estrogenization" in conditions like cirrhosis of the liver, hyperthyroidism, aging, obesity
  • Present in adipose cells, liver, skin, and other tissues
• Calcitriol (1,25(OH)2-D3) Synthesis


  1. Precursors - Fish liver oil and egg yolk

  2. Produced in the malphigian layer of the epidermis from 7-dehydrocholesterol in an ultraviolet light-mediated, nonenzymatic photolysis reaction

  3. Transported by vitamin D-binding protein to the liver for 25-hydroxylation

  4. 25-hydroxylation occurs in the endoplasmic reticulum and requires magnesium, NADPH, molecular oxygen, and uncharacterized cytoplasmic factor

  5. Enzymes involved - NADPH-dependent cytochrome P450 reductase, Cytochrome P450

  6. 25(OH)2-D3 - weak agonist, must be modified by hydroxylation at position C1 in the kidney mitochondria for full biologic activity
• Steroidogenesis


  The process of converting progesterone to other steroid hormones
• Estrogenization


  Increased activity of aromatase may contribute to this
• Conditions that may increase aromatase activity


  • Cirrhosis of the liver
  • Hyperthyroidism
  • Aging
  • Obesity
• Tissues where aromatase is present


  • Adipose cells
  • Liver
  • Skin
  • Other tissues
• Precursors for 1,25(OH)2-D3


  Fish liver oil and egg yolk
• Production of 1,25(OH)2-D3 (calcitriol)


  Produced in the malphigian layer of the epidermis from 7-dehydrocholesterol in an ultraviolet light-mediated, nonenzymatic photolysis reaction
• Vitamin D-binding protein


  Specific transport protein that binds to vitamin D3 and moves it from the skin or intestine to the liver
• 25-hydroxylation


  Occurs in the endoplasmic reticulum and requires: Magnesium, NADPH, Molecular oxygen, Uncharacterized cytoplasmic factor
• Enzymes involved in 25-hydroxylation


  • NADPH-dependent cytochrome P450 reductase
  • Cytochrome P450
• 25(OH)2-D3


  Weak agonist, must be modified by hydroxylation at position C1 for full biologic activity
• Conversion of 25(OH)2-D3 to 1,25(OH)2-D3 (calcitriol)


  Accomplished in the mitochondria of the renal proximal convoluted tubule, requires: NADPH, Magnesium, Molecular oxygen, At least 3 enzymes (Flavoprotein - renal ferredoxin reductase, Cytochrome P450, Iron-sulfur protein - renal ferredoxin)
• Hormones classified as catecholamines, thyroid hormones, and larger peptide precursors

  • Dopamine
  • Norepinephrine
  • Epinephrine
  • T3
  • T4
  • Insulin
  • PTH
  • Angiotensin II
  • POMC
• Catecholamines


  • Synthesized from tyrosine in the chromaffin cells of the adrenal medulla
  • Epinephrine is the major product of the adrenal medulla, constituting about 80% of the catecholamines
  • Epinephrine is not made in extramedullary tissue
• Conversion of tyrosine to epinephrine

  1. Ring hydroxylation

  2. Decarboxylation

  3. Side-chain hydroxylation to form norepinephrine

  4. N-methylation to form epinephrine
• Tyrosine hydroxylase


  Rate-limiting enzyme in catecholamine biosynthesis, found in both soluble and particle-bound forms only in tissues that synthesize catecholamines, functions as an oxidoreductase with tetrahydropteridine as cofactor
• Catecholamines cannot cross the blood brain barrier, so in the brain they must be synthesized locally
• 1. DOPA


  Precursor of dopamine that readily crosses the blood brain barrier, important in the treatment of Parkinson's Disease