2. Hormones Structure and General Properties.pdf
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HORMONES General Structure and Properties Asst. Prof. Betül ÖZBEK [email protected] 2023-2024 Introduction to Hormones o The nervous system and the endocrine system provide intercellular, organism-wide communication. The endocrine system su...
HORMONES General Structure and Properties Asst. Prof. Betül ÖZBEK [email protected] 2023-2024 Introduction to Hormones o The nervous system and the endocrine system provide intercellular, organism-wide communication. The endocrine system supplied hormones, which are mobile messages. o As classically defined, a hormone is a substance that is synthesized in one organ and transported by the circulatory system to act on another tissue. o However, this is too restrictive because hormones can act on adjacent cells (paracrine action) and on the cell in which they were synthesized (autocrine action) without entering the systemic circulation. 2 Introduction to Hormones o A given hormone can affect several different cell types; that more than one hormone can affect a given cell type; and that hormones can exert many different effects in one cell or in different cells. o Hormones are present at very low concentrations in the extracellular fluid, generally in the femto- to nanomolar range (10−15-10−9 mol/L). 3 Hormones Can Be Classified In Several Ways Hormones can be classified according to 1. Chemical composition, 2. Solubility properties, 3. Location of receptors, and 4. The nature of the signal used to mediate hormonal action within the cell. 4 Hormone Classification_Chemical Composition Hormones are synthesized from A. Cholesterol C. Protein/Peptides of various sizes i. Glucocorticoids (C21), i. Thyrotropin-releasing hormone ii. Mineralocorticoids (C21), (TRH), iii. Androgens (C19), ii. Adrenocorticotropic hormone iv. Estrogens (C18), (ACTH) v. Progestins (C21), iii. Parathyroid hormone (PTH) vi. 1,25(OH)2-D3 iv. Growth hormone (GH) v. Insulin B. Amino acids 1. Tyrosine derivatives; D. Glycoproteins i. Thyroid hormones (T3, i. Follicle-stimulating hormone (FSH), triiodothyronine; T4, thyroxine) ii. Luteinizing hormone (LH), ii. Catecholamines (Dopamine, iii. Thyroid-stimulating hormone (TSH), Adrenaline, Noradrenaline) iv. Chorionic gonadotropin (CG) 2. Tryptophan derivatives; i. Serotonin ii. Melatonine 5 Hormone Classification_Chemical Composition 6 Hormone Classification_Solubility and Receptor Location 8 Hormone Classification_Solubility and Receptor Location Group I (Class I) Group II (Class II) o The hormones are lipophilic. o The hormones are water-soluble (generally peptide structure). o Because they are lipophilic, after secretion, these hormones associate with plasma o They don’t need a carrier protein in the transport or carrier proteins in the circulation. circulation. o Binding to a protein increases the half-life (t1/2) of the hormone. o Thus their half-lives (t1/2) are shorter. o Biologically active form is the free hormone. o After reaching to their target cell they bind to their specific receptors (on the plasma o After reaching to its target cell, bound membrane) spanning the plasma membrane. hormone is released from its carrier protein and free form readily traverses the lipophilic o Hormones that bind to these surface receptors plasma membrane and encounters receptors of cells communicate with intracellular in either the cytosol or nucleus. metabolic processes through intermediary molecules called second messengers (the o The ligand-receptor complex is the hormone itself is the first messenger), which intracellular messenger in this group. are generated as a consequence of the ligand- receptor interaction. 9 Receptors o Polypeptide/protein hormones and the catecholamines bind to receptors located on the plasma membrane. This interaction generate a secondary messenger or a signal that regulates various intracellular functions, often by changing the activity of an enzyme. o The lipophilic steroid, retinoid, and thyroid hormones interact with intracellular receptors. This interaction directly provides the signal, generally affects the transcription rate of specific genes. 10 Hormone Classification_Nature of Signal Used 11 Hormones Are Synthesized & Modified for Full Activity in a Variety of Ways o Hormones derived from cholesterol are synthesized in final form and secreted immediately. o Catecholamines, are synthesized in final form and stored in the producing cells. o Hormones like insulin, are synthesized as precursor molecules in the producing cell, and then are processed and secreted upon a physiologic cue (plasma glucose concentrations). o T3 and DHT (dihydrotestosterone) are converted to their active forms from precursor molecules in the peripheral tissues. 12 Adrenal Steroidogenesis o Adrenal gland has 2 different parts: 1. Adrenal Cortex: Glucocorticoids, Mineralocorticoids and Androgens (adrenal steroid hormones) 2. Adrenal Medulla: Epinephrine, Norepinephrine, and Dopamine (Catecholamines) o The adrenal steroid hormones are synthesized from cholesterol. o Upon stimulation of the adrenal by ACTH, free cholesterol is transported into the mitochondrion, and it is converted to pregnenolone (first product) by cytochrome P450 side chain cleavage enzyme (P450scc). Reaction requires O2 and NADPH o An ACTH-dependent steroidogenic acute regulatory (StAR) protein is essential for the transport of cholesterol into the inner mitochondrial membrane (rate-limiting step). 13 Adrenal Steroidogenesis o The adrenal steroid hormones are synthesized from cholesterol. o Most of the cholesterol in the adrenal is esterified and stored in cytoplasmic lipid droplets. o Upon stimulation of the adrenal by ACTH, an esterase is activated, and the free cholesterol formed is transported into the mitochondrion, where a cytochrome P450 side chain cleavage enzyme (P450scc) converts cholesterol to pregnenolone (first product). o Cleavage of the side chain involves sequential hydroxylations, followed by side chain cleavage to give the 21-carbon steroid. 14 Adrenal Steroidogenesis o All mammalian steroid hormones are formed from cholesterol via pregnenolone through a series of reactions that occur in either the mitochondria or endoplasmic reticulum of the producing cell. 15 Adrenal Steroidogenesis 16 Adrenal Steroidogenesis o Aldosterone is the most potent natural mineralocorticoid in humans. Increase Na+ reabsorption (retention) and K+ excretion in the kidneys. Major stimulators of aldosterone are the renin-angiotensin system (angiotensinogen II) and K+ concentration. Other stimulators of the aldosterone are ACTH and Na+ concentration. o Cortisol is the most potent natural glucocorticoid hormone in humans. Stimulates gluconeogenesis Inhibits the immune response o Steroidogenesis involves the repeated shuttling of substrates in and out of the mitochondria. 18 Adrenal Steroidogenesis o Glycocorticoid Transport The main plasma binding protein is transcortin, or corticosteroid-binding globulin (CBG). CBG binds most of the hormone when plasma cortisol levels are within the normal range. o Gonadal Steroid Transport Testosterone is carried in the circulation by sex hormone–binding globulin (SHBG) or testosterone-estrogen–binding globulin (TEBG), Estrogens are bound to SHBG and progestins to CBG. o These binding proteins provide a circulating reservoir of hormones. 20 Androgen Synthesis o The major androgen or androgen precursor the adrenal cortex produces is dehydroepiandrosterone (DHEA). o DHEA is a prohormone it is converted into the more potent androstenedione. o Reduction of androstenedione results in the formation of testosterone, the most potent adrenal androgen. Small amounts of testosterone are produced in the adrenal by this mechanism, but most of this conversion occurs in the testes (Leydig cells). o The conversion of cholesterol to pregnenolone is identical in the adrenal, ovary, and testis. However, LH promotes the reaction in the latter two tissues rather than ACTH. 22 Testosterone o Testosteron can be considered a prohormone o Some estradiol is formed from and metabolized by two pathways. the peripheral aromatization of testosterone, particularly in o It is converted into its more potent metabolic males. compound Dihydrotestosterone (DHT). o Most of this conversion occurs outside the testes, a reaction catalyzed by the NADPH- dependent 5α-reductase. 23 Ovarian Steroidogenesis o 17β-Estradiol is the primary estrogen of ovarian origin. o In pregnancy, relatively more estriol is produced, and this comes from the placenta. o Estrogens are formed by the aromatization of androgens. The aromatase enzyme complex is thought to include a P450 monooxygenase. Estradiol is formed if the substrate of this enzyme complex is testosterone, whereas estrone results from the aromatization of androstenedione. o Progesterone, a precursor for all steroid hormones, is produced and secreted by the corpus luteum. 25 1,25(OH)2-D3 (Calcitriol) o The active molecule 1,25(OH)2-D3, is synthesized from 7-dehyrocholesterol, and transported to other organs where it activates biologic processes in a manner similar to that employed by the steroid hormones. 27 1,25(OH)2-D3 (Calcitriol) Synthesis o Skin Most of the precursor for 1,25(OH)2-D3 synthesis is produced in the malpighian layer of the epidermis from 7-dehydrocholesterol in an ultraviolet light–mediated, nonenzymatic photolysis reaction. o Liver A specific transport protein called the vitamin D–binding protein binds vitamin D3 and its metabolites and moves vitamin D3 from the skin or intestine to the liver, where it undergoes 25-hydroxylation. The 25(OH)-D3 enters the circulation, where it is the major form of vitamin D found in plasma, and is transported to the kidney by the vitamin D–binding protein. o Kidney Hydroxylation at position C1 produces 1,25(OH)2-D3, which is the most potent naturally occurring metabolite of vitamin D. 28 Tyrosine Derivatives_Catecholamine Synthesis o Three amines i. dopamine, ii. norepinephrine, and iii. epinephrine are synthesized from tyrosine in the chromaffin cells of the adrenal medulla. o The major product of the adrenal medulla is epinephrine. 80% of the catecholamines in the medulla is epinephrine, and it is not made in extramedullary tissue. o In contrast, most of the norepinephrine present in organs innervated by sympathetic nerves is made in situ (about 80% of the total). 29 Tyrosine Derivatives_ Catecholamine Synthesis o The conversion of tyrosine to epinephrine requires four sequential steps: 1) Ring hydroxylation_ tyrosine hydroxylase 2) Decarboxylation_DOPA decarboxylase 3) Side chain hydroxylation to form norepinephrine_Dopamine -oxidase 4) N-methylation to form epinephrine_PNMT L-dopa: L-dihydroxyphenylalanine PNMT: phenylethanolamine-N-methyltransferase 30 Tyrosine Derivatives_T3 & T4 Hormone Synthesis o Synthesis is regulated by the TSH hormone. o Triiodothyronine (T3) and tetraiodothyronine (thyroxine; T4) hormones require rare element iodine for bioactivity. o They are synthesized as part of a precursor (prohormone) molecule called thyroglobulin. o After the synthesis, T3 and T4 are stored in an intracellular reservoir (colloid). o TSH stimulus causes exocytosis of those hormones into the circulation. o One-half to two-thirds of T4 and T3 in the body is in an extrathyroidal reservoir. Most of these hormones circulate in the blood in bound form to a specific binding protein called thyroxine-binding globulin (TBG). 31 o DIT, diiodotyrosine o MIT, monoiodotyrosine o Tgb, thyroglobulin Tyrosine Derivatives_ o T3, triiodothyronine T3 & T4 Hormone Synthesis o T4, thyroxine o Asterisks indicate steps or processes where inherited enzyme deficiencies cause congenital goiter and often result in hypothyroidism. 32 Tyrosine Derivatives_T3 & T4 Hormone Synthesis o Na+-K+-ATPase–dependent thyroidal I− transporter: The ratio of iodide in thyroid to iodide in serum (T:S ratio) is a reflection of the activity of this transporter. This activity is primarily controlled by TSH. o Thyroglobulin (prohormone) is iodinated than glycosylated to form T4 and T3. 70% of the iodide in thyroglobulin exists in the inactive precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT), 30% is in the metabolically active form of iodothyronine residues, T4 and T3. o The coupling of two DIT molecules to form T4—or of an MIT and DIT to form T3—occurs within the thyroglobulin molecule. o EvenT3 synthesis occurs in the thyroid gland major amounts are produced in peripheral tissues. A peripheral deiodinase in target tissues such as the pituitary, kidney, and liver selectively removes I− from T4 to make a much more active form of thyroid hormone which is T3. 33 Tryptophan Derivatives_Serotonin & Melatonin Synthesis 35 Protein/Peptide Hormones o Several hormones are made from larger peptide precursors Insulin Parathyroid Hormone (PTH) Angiotensin II Pro-opiomelanocortin (POMC) protein o They are produced in pre-prohormone structure in ribosomes. 37 Insulin o Insulin (a polypeptide hormone) is synthesized as a preprohormone in the pancreatic beta cells. o After removal of pre- part in the endoplasmic reticulum lumen pro-insulin is obtained. o Pro-insulin is the inactive form. o Then pro-insulin molecule undergoes a series of site-specific peptide cleavages in the Golgi apparatus that result in the formation of equimolar amounts of mature insulin and C-peptide. o When the blood glucose concentration exceeds the normal ranges, insulin hormone is released into circulation to show its metabolic effects. o C-peptide is the marker for endogenous insulin. 38 Renin-Angiotensin-Aldosteron System o This system is activated when the blood pressure is decreased. o Biologically active forms of angiotensin (Ang) are Ang II and Ang III. o Angiotensinogen precursor is catalyzed by renin enzyme (synthesized in juxtaglomerular cells of the kidney), to produce angiotensin I. o Angiotensin-converting enzyme (ACE), a glycoprotein found in the lung, endothelial cells, and plasma, forms angiotensin II from angiotensin I. o Angiotensin II inhibits renin release and stimulates aldosterone (the most potent natural mineralocorticoid) production. This results in Na+ retention, volume expansion, and increased blood pressure. 39 Angiotensin II 40 Variations In The Storage & Secretion of Hormones o Steroid hormones and 1,25(OH)2-D3 Synthesized in their final active form Secreted as they are made, thus there is no intracellular reservoir of these hormones. o Catecholamines Synthesized in active form, Stored in granules in the chromaffin cells in the adrenal medulla. In response to appropriate neural stimulation, these granules are released from the cell through exocytosis, and the catecholamines are released into the circulation. A several-hour reserve supply of catecholamines exists in the chromaffin cells. o PTH Exists in storage vesicles. When Ca2+ levels are high in the parathyroid cell, proPTH is degraded and stored. PTH is secreted when Ca2+ is low in the parathyroid cells, which contain a several-hour supply of the hormone. 42 Variations In The Storage & Secretion of Hormones o Insulin 15 to 20% of the hormone is stored in the β cells of the pancreas. Insulin and the C-peptide are normally secreted in equimolar amounts. Stimuli such as glucose, which provokes insulin secretion, therefore trigger the processing of pro-insulin to insulin. o T3 and T4 A several-week supply of T3 and T4 exists in the thyroglobulin that is stored in colloids in the lumen of the thyroid follicles. These hormones can be released upon stimulation by TSH. 43 References 1. Harpers Illustrated Biochemistry, 31st edition, 2018 2. Lehninger Principles of Biochemistry, 8th edition, 2021 3. Lippincott Illustrated Reviews Biochemistry, 7th edition, 2017 44
