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Molecular endocrine2

  1. By Dr Khaled S. Algariri MOLECULAR ENDOCRINOLOGY -2-
  2. BIOSYNTHESIS OF HORMONES Most commonly, hormones are categorized into four structural groups:  Peptides and Proteins  Steroids  Amino Acid Derivatives  Fatty Acid Derivatives
  3. 1. Peptide and Protein 1. Steroids 1. Amino acid derivatives 1. Fatty acid derivatives Insulin Testosterone Epinephrine Eicosanoids- prostaglandins, prostacyclins, leukotrienes and thromboxanes. Glucagon Estrogen Nor-epinephrine ACTH Progesteron Thyroxine TSH Cortisol Thyrotropin releasing hormone Aldosteron
  4. 1- Peptides and Proteins Hormones Biosynthesis Protein and peptide hormones are encoded in genes, with each hormone usually represented only once in the genome. The genes are transcribed in the nucleus and undergo transcriptional processing to yield mature mRNA, which is then transported from nucleus to the cytoplasm. On export from the nucleus, the mRNA transcripts attach to ribosomes, where they are translated into protein.
  5.  Several important peptide hormones are secreted from the pituitary gland. The anterior pituitary secretes three: prolactin, which acts on the mammary gland; adrenocorticotropic hormone (ACTH), which acts on the adrenal cortex to regulate the secretion of glucocorticoids; and growth hormone, which acts on bone, muscle, and the liver. The posterior pituitary gland secretes antidiuretic hormone, also called vasopressin, and oxytocin
  6. Protein/Peptide hormones are synthesized in endoplasmic reticulum, transferred to the Golgi and packaged into secretory vesicles for export. They can be secreted by one of two pathways:  Regulated secretion: The cell stores hormone in secretory granules and releases them in "bursts" when stimulated. This is the most commonly used pathway and allows cells to secrete a large amount of hormone over a short period of time.  Constitutive secretion: The cell does not store hormone, but secretes it from secretory vesicles as it is synthesized
  7. 2-Steroid hormones  Steroid hormones are not water soluble so have to be carried in the blood complexed to specific binding globulins.  Corticosteroid binding globulin carries cortisol  Sex steroid binding globulin carries testosterone and estradiol  In some cases a steroid is secreted by one cell and is converted to the active steroid by the target cell: an example is androgen which secreted by the gonad and converted into estrogen in the brain
  8. Steroid Hormones  Steroid hormones are nonpolar (no net charge), and can thus diffuse across lipid membranes (such as the plasma membrane). They leave cells shortly after synthesis. phospholipid Polar substances are water soluble (dissolve in water), nonpolar substances are lipid soluble.
  9. Functions of Steroid Hormones  Steroid hormones play important roles in: - carbohydrate regulation (glucocorticoids) - mineral balance (mineralocorticoids) - reproductive functions (gonadal steroids)  Steroids also play roles in inflammatory responses, stress responses, bone metabolism, cardiovascular fitness, behavior, cognition, and mood.
  10. How does the synthesis of steroids differ from that of peptide hormones? • While peptide hormones are encoded by specific genes, steroid hormones are synthesized from the enzymatic modification of cholesterol. • Thus, there is no gene which encodes aldosterone, for example. • As a result: - There are far fewer different types of steroid hormones than peptide hormones. - Steroid structures are the same from species to species - The regulation of steroidogenesis involves control of the enzymes which modify cholesterol into the steroid hormone of interest.
  11. The Role of Cholesterol in Steroid Synthesis  The first enzymatic step in the production of ANY steroid hormone begins with enzymatic modification of cholesterol
  12. Sources of Cholesterol for Steroid Synthesis  Cholesterol can be made within the cell from acetyl CoA (de novo synthesis).  This is a multistep process, involving many enzymatic reactions.  A key rate-limiting enzyme is HMG-CoA reductase.  There is negative feedback regulation of HMG-CoA reductase activity by cholesterol, so that high intracellular cholesterol inhibits de novo synthesis. acetyl CoA HMG-CoA mevalonate cholesterol HMG-CoA reductase
  13. Sources of Cholesterol for Steroid Synthesis  Cholesterol is also taken up by the cell in the form of low density lipoprotein (LDL). - LDL is a complex composed of cholesterol, phospholipids, triglycerides, and proteins (proteins and phospholipids make LDL soluble in blood). - LDL is taken into cells via LDL receptors, and broken down into esterified cholesterol, and then free cholesterol: LDL receptor LDL esterified cholesterol free cholesterol
  14.  The amount of free cholesterol in the cell is maintained relatively constant: Source of Cholesterol for Steroid Synthesis steroid synthesis free cholesterol level esterified cholesterol level cellular synthesis of cholesterol LDL
  15. Cellular Localization of Cholesterol Metabolism for Steroid Production  The first enzymatic step in steroid synthesis is the conversion of cholesterol into pregnenolone.  The enzyme that catalyzes this reaction is located in the inner mitochondrial membrane.
  16. Steroid hormone synthesis All steroid hormones are derived from cholesterol. A series of enzymatic steps in the mitochondria and ER of steroidogenic tissues convert cholesterol into all of the other steroid hormones and intermediates. The rate-limiting step in this process is the transport of free cholesterol from the cytoplasm into mitochondria. This step is carried out by the Steroidogenic Acute Regulatory Protein (StAR)
  17. Transport of Cholesterol  Cholesterol is lipid soluble, and mostly located associated with the external mitochondrial membrane.  The conversion of cholesterol to steroids occurs in the internal mitochondrial membrane.  Now, to see if you have been paying attention…  How does cholesterol get from the external membrane to the internal membrane?  Answer: Steroidogenic acute regulatory protein (StAR), which transports cholesterol into the mitochondria, moving it from the outer membrane to the inner membrane.
  18. 3. Amino Acid Derivatives  There are two groups of hormones derived from the amino acid tyrosine:  Thyroid hormones are basically a "double" tyrosine with the critical incorporation of 3 or 4 iodine atoms.  Catecholamines include epinephrine and norepinephrine, which are used as both hormones and neurotransmitters.  The pathways to synthesis of these hormones is provided in the sections on the thyroid gland and the adrenal medulla.
  19. The circulating halflife of thyroid hormones is on the order of a few days. They are inactivated primarily by intracellular deiodinases. Catecholamines, on the other hand, are rapidly degraded, with circulating halflives of only a few minutes.  Two other amino acids are used for synthesis of hormones:  Tryptophan is the precursor to serotonin and the pineal hormone melatonin  Glutamic acid is converted to histamine
  20. 4. Fatty Acid Derivatives - Eicosanoids Eicosanoids are a large group of molecules derived from polyunsaturated fatty acids. The principal groups of hormones of this class are prostaglandins, rostacyclins, leukotrienes and thromboxanes.  Arachadonic acid is the most abundant precursor for these hormones. Stores of arachadonic acid are present in membrane lipids and released through the action of various lipases. The specific eicosanoids synthesized by a cell are dictated by the battery of processing enzymes expressed in that cell.  These hormones are rapidly inactivated by being metabolized, and are typically active for only a few seconds
  21. Mechanism of Hormone action The hormones fall into two general classes based on their solubility in water.  1. Hydrophilic Hormone: The water soluble hormone. They are transported simply dissolved in blood  Examples: the catecholamines (epinephrine and norepinephrine) and peptide/protein hormones.  2. Lipophilic Hormone: They are poorly soluble in water. So they cannot be dissolved in watery blood. They bind to plasma protein and present in the blood in protein bound form. They are lipid soluble.  Examples: The lipid soluble hormones include thyroid hormone, steroid hormones and Vitamin D3
  22. Types of Receptors To initiate their effect, hormones must bind with the target cell receptor. Interaction between hormone and target receptor produce transduction and amplification of signal leading to cellular response. The mechanism of hormone action depends on type of receptor and also on the solubility of hormone.  1. Cell Surface Receptors: Receptors for the water soluble hormones are found on the surface of the target cell, on the plasma membrane. These types of receptors are coupled to various second messenger systems which mediate the action of the hormone in the target cell.  2. Cytosolic or Intracellular receptors: Receptors for the lipid soluble hormones reside in the nucleus (and sometimes the cytoplasm) of the target cell. Because these hormones can diffuse through the lipid bilayer of the plasma membrane, their receptors are located on the interior of the target cell
  23. General means of hydrophilic and lipophilic Hormone action  1. Surface binding hydrophilic hormone acts largely via activating 2nd messenger pathways. This leads to a series of events involving protein kinases/or phosphatases and finally acting on target enzyme so as evoke cellular response.  2. Lipophilic hormone function mainly by activating through the nuclear gene affecting transcription. It leads to formation of proteins for desired cellular response.
  24. I. Types of cell surface receptor  1. Ion-channel coupled receptor  2. The G-Protein coupled receptor(GPCR mediated hormone response)  2.1. C-AMP System- elaborate with example of Epinephrine  2.2. The calcium ion: calmodulin system  3. Enzyme coupled receptor mediated hormone response  3.1. Tyrosine kinase receptor-elaborate with example of insulin
  25. Signal amplification vi 2nd messenger pathways Initial signal is in the form of hormone which acts as ligand whose concentration is just one/per receptor. The hormonal response has got multiple steps, and each step multiplies the signal (cascading effect) that finally leading to million fold amplification, i.e. one hormone molecule mediating its effect through million of molecules. This process is known as signal amplification.
  26. STEPS OF ACTION OF HORMONES  Step1: Free lipophilic hormone (hormone not bound with its plasma protein carrier) diffuses through the plasma membrane of the target cell and binds with the receptor which is intracellularly located inside the cytosol/or in the nucleus.  Step2. Each receptor has specific binding region with hormone and another region with binding with DNA. Receptor alone cannot bind to DNA unless it binds to hormone. Once the hormone is bound to receptor, the hormone receptor complex binds to specific region of DNA known as Hormone response element(HRE).  Step3: Transcription of gene  Step4: m RNA transported out of nucleus into the cytoplasm  Step5: Translation at Ribosome  Step6: Protein/enzyme released from ribosome  Step7: protein/enzyme mediate ultimate response
  27. Steroid Hormones: Molecular Action
  28. Lipophilic hormone response mediated through Cytosolic receptor/nuclear receptor
  29. Mechanism of thyroid hormone action  Receptors for thyroid hormones are nuclear and its affinity is tentimes higher for T3 than T4  The amount of nuclear receptors is very low  Four variants of nuclear receptor were observed and mitochondrial receptor for T3 was also described  Free thyroid hormone receptor (TR) without bound hormone is bound to hormone response element of DNA (HRE) and corepressor (CoR)  After binding T3 to receptor - CoR is liberated and coactivators (CoA) is bound and the transcription to mRNA begins
  30. Mechanism of thyroid hormone receptor action. The thyroid hormone receptor (TR) and retinoid X receptor (RXR) form heterodimers that bind specifically to thyroid hormone response elements (TRE) in the promoter regions of target genes. In the absence of hormone, TR binds co-repressor (CoR) proteins that silence gene expression. The numbers refer to a series of ordered reactions that occur in response to thyroid hormone: (1) T4 or T3 enters the nucleus; (2) T3 binding dissociates CoR from TR; (3) Coactivators (CoA) are recruited to the T3-bound receptor; (4) gene expression is altered.