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Biochemistry of Hormones

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Biochemistry of Hormones به نام خدا Biochemistry of Hormones Chapter 1 & 22 Dr. Sajadi Hormones: An Introduction Hormone: [hormon, the present participle of impel, or set in motion] Endocrinology: Endocrine: [Endo (internal or within) and Krinein (separate)] The study of hormones, their receptors and the intracellular signaling pathways. • Receptor → The immediate recipient of the hormone • Receptor–hormone interaction → signal transduction → specific biological response(s). • The biochemical era of endocrinology began in approximately 1955–1960. Hormones and Their Communication Systems 1. Types of Hormone Molecules Hormones are heterogeneous in their molecular size, chemical properties, and pathways of synthesis. Peptide or protein hormones range from 3 aa (TRH) to over 100 per subunit. Amino acid-derived hormones: Thyroid hormone and Epinephrine are derived from tyrosine. Steroid hormones: Vitamin D and its metabolites are derived from cholesterol or 7-dehydrocholesterol, respectively. Prostaglandins and other eicosanoids derived from arachidonic acid, cleaved from membrane phospholipids, as the main precursor. Classes of Hormones 2. Types of Hormonal Communication Systems • Endocrine: Releasing of hormone into general circulation. Hypothalamic-releasing hormones • Paracrine: Decreased distance and no dilution in circulation Most prostaglandins Several steroid hormones (testestrone) IGF-1 • Autocrine: Some cells both produce and respond to the same hormone. Growth factors from malignant cells Acronyms of some hormones Hormones and the Hormonal Cascade System Peptides (proteins) Hormones Products of translation Variable size: [3aa (TRH)- multisubunit glycoproteins] • Variations in modifications to mRNA and/or protein leads to deviation from the original “one gene, one protein” concept. 1. Alternative processing of a single primary transcript: The production of either calcitonin (CT) or calcitonin-gene-related peptide (CGRP). 2. Post-translational processing of the initial protein product. Proteolytic cleavage by a family of proprotein convertases (PC1–PC7). a. PTH (84 aa)→ from removing of pre- and pro-sequences of 25 and 6 aa. b. Proopiomelanocortin differentially processed in different cell type. c. TRH contain several copies of a single peptide hormone. d. Insulin Important Polypeptide Hormones in the Body and their Actions Post translational processing (cleavage) events ENK Proopiomelanocortin is a Precursor Polypeptide for several Hormones • Products are expressed in separate cells based on their content of specific proteases required to cleave polypeptides, specific metabolic control and the presence of positive regulators. Summary of Stimuli and Products of Proopiomelanocortin Proteolytic maturation of Posterior pituitary (neurohypophysis) hormones • Vasopressin and neurophysin II are released by the activity of baroreceptors and osmoreceptors, which sense a fall in blood pressure or a rise in extracellular sodium ion concentration, respectively. • Release of vasopressin-neurophysin II can be stimulated by administration of nicotine. • Oxytocin and neurophysin I are released from the posterior pituitary by the suckling response in lactation females or by other stimuli mediated by a specific cholinergic mechanism. • Oxytocin–neurophysin I release can be triggered by injection of estradiol. Multiple copies of a hormone can be encoded on a single gene Hypothalamic Releasing Hormones Anterior pituitary hormone (Trophic=Tropin=Tropic hormones) Amino acid derivatives Derivatives of Tyr: • Thyroid hormones Double Tyr with 3 or 4 Iodine hormone Half-life is about a few days. • Catecholamines Epinephrine and Norepinephrine used as both hormones and neurotransmitters. Derivatives of Trp: • Serotonin • Melatonin Derivatives of His: • Histamine Synthesis of Amino Acid Derived Hormones • Epinephrine is synthesized from Phenylalanine/Tyrosine • The synthesis of epinephrine occurs in the adrenal medulla. • Secretion of epinephrine is signaled by the neural response to stress, which is transmitted to adrenal medulla by way of a preganglionic acetylcholinergic neuron. • Cortisol becomes elevated in the medulla and induces phenylethanolamin e N- methyltransferase (PNMT), a key enzyme catalyzing conversion of norepin ephrine to epinephrine. • Epinephrine once secreted, affects α-receptors of hepatocytes to increase blood glucose level; α- receptor on vascular smooth muscle cells and on pericytes to cause cellular contraction and increase blood pressure. Epinephrine biosynthesis CHEMISTRY OF THE THYROID HORMONES • Thyroxine (T4; 3,5,3′,5′-tetraiodothyronine) • Triiodothyronine (T3; 3,5,3′-triiodothyronine) Structure of thyroid Gland • 20–30 million follicles in thyroid gland • Each thyroid follicle : a single layer of epithelial cells + a lumen filled with colloid • Colloid is composed of granules and protein thyroglobulin. • The effects of thyroid hormone: (a) on cellular differentiation and development, particularly nervous system (b) metabolic pathways through which the body uses carbohydrates, lipids, and proteins. • Monoiodotyrosine (MIT), Diiodotyrosine (DIT), Tetraiodo-L-thyronine or Thyroxine (T4)and Triiodo-L-thyronine (T3) are produced within thyroglobulin (TG). • The iodinated amino acids and thyronines are stored in the thyroid follicle as part of thyroglobulin. • There are hot spots (regions for very active iodination) in the thyroglobulin sequence for the incorporation of iodine: 1. Glu/AspTyr, associated with the synthesis of thyroxine or iodotyrosines. 2. Ser/ThrTyrSer, associated with the synthesis of iodothyronine and iodotyrosine. 3. Glu-X-Tyr, associated with the remaining iodotyrosyls in the sequence. SYNTHESIS AND SECRETION OF THYROID HORMONES • Steps for the synthesis and secretion of T4 and T3 (in thyrocyte): 1. Active transport of iodide into the thyroid gland follicular cells; 2. Oxidation of iodide and iodination of tyrosyl residues within the protein thyroglobulin; 3. Transfer and coupling of iodotyrosines within thyroglobulin to form T4 and T3 ; 4. Storage of thyroglobulin as the colloid in the lumen of the thyroid follicle; 5. Endocytosis of the colloid back into the thyroid epithelial cell; 6. Proteolysis of thyroglobulin with concomitant release of T4 and T3 as well as free iodotyrosines and iodothyronines; 7. Secretion of T4 and T3 into the blood; 8. Deiodination of iodotyrosines within the thyroid follicular cells for reutilization of the liberated iodine. Synthesis of Thyroid Hormone Requires Incorporation of Iodine into a Tyrosine of Thyroglobulin Thyroid hormone Inactivation and Degradation of Hormones • Most polypeptide hormones are degraded to amino acids by hydrolysis, which presumably occurs in the lysosome. • Partial hydrolysis by proteinases is a principal pathway for degradation. • Some of the releasing hormones have either or both of amino acid derivatives of the cyclic glutamate ring at N-terminal and C-terminal amide. • Breakage of or cleavage of these derivatives lead to inactivation of many of hormones and such enzymic activities have been reported in blood. • Hormones Containing a Cystine Disulfide Bridge may be degraded initially by the random action of Cystine aminopeptidase and Glutathione transhydrogenase. • Maturation of prohormones in many cases involves proteolysis, which may be considered as a degradation process that the prohormone is degraded to active forms. Inactivation and Degradation of Hormones • Hypothalamic Releasing Hormones Containing an N-terminal Pyroglutamate, a C-Terminal Amino Acid Amide, or Both Control of secretion Feedback loop • Serum Ca+2 →Controlling PTH • Blood Glc→Insulin Cyclic Hormonal Cascade Systems • Hormonal cascade systems can be generated by external signals and by internal signals. • The diurnal variations in levels of cortisol secreted from the adrenal gland probably initiated by serotonin and vasopressin. • The day and night variations in the secretion of melatonin from the pineal gland and the internal regulation of the ovarian cycle. • Some of these biorhythms operate on a cyclic basis, often dictated by daylight and darkness, and are referred to as chronotropic control of hormone secretion. Melatonin and Serotonin Synthesis Are Controlled by Light and Dark Cycles • The release of melatonin from the pineal gland is an example of a biorhythm. • Control is exerted by light entering the eyes and is transmitted to the pineal gland by way of the CNS. • The adrenergic neuron innervating the pinealocyte is inhibited by light transmitted through the eyes. • Norepinephrine released as a neurotransmitter in the dark stimulates cAMP formation through a β receptor in the pinealocyte cell membrane. • The increased activity of N-acetyltransferase causes the conversion of serotonin to N- acetylserotonin. • Hydroxyindole O methyltrnasferas (HIOMT) catalyzes the conversion of N-acetylserotonin to melatonin, which is secreted in the dark hours but not during light hours. • Melatonin is circulated to cells containing receptors that generate effects on reproductive and other functions. • For example, melatonin has been shown to exert an antigonadotropic effect. Activity of Vasopressin: Protein Kinase A • Activity of arginine vasopressin (AVP) on the distal kidney cell is mediated by the activation of the protein kinase A pathway. • The high extracellular salt concentration causes shrinkage of osmoreceptor cell and generates an electrical signal transmitted down the axon of the osmoreceptor to the cell body of the VP neuron generating an action potential. • The
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