LECTURE 4. Hormones and mechanisms of their influence on metabolic processes Room 409, the 3d floor, Educational Building № 12, Faculty of Veterinary Medicine, lilkalachnyuk@gmail.com 1 Thematic Module 4. Regulatory effects of inorganic and organic substances on the metabolism LECTURE 4 Hormones and mechanisms of their influence on metabolic processes prolactin Hormones as Regulators of metabolism Common characteristics of hormones and their molecular structure, biosynthesis, and metabolism. Mechanisms of hormonal influence on metabolic processes Principles of hormone action Depending on the type of hormone, hormone signals are transmitted to the target cells in different ways. Polar (hydrophilic) hormones act on the external cell membrane, while apolar (lipophilic) hormones penetrate the cell and act in the cell nucleus. 2 Hormones are chemicals released by a cell or a gland in one part of the body which send out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one cell to another. All multi-cellular organisms produce hormones; plant hormones are also called phytohormones. 3 Epinephrine is more of a hormone than a neurotransmitter: the main place of synthesis is the adrenal medulla. Regulation of secretion of epinephrine is carried out under effect of nervous system. The level of epinephrine increases dramatically under the influence of stress factors (fear, physical, mental overload). Metabolic regulation is carried out under the influence of changes in the concentration of glucose in the blood, in particular, hypoglycemia stimulates the secretion of epinephrine. The mechanism of action of epinephrine is bonded to “adenylate cyclase effect” (see above, slide 7) and its interaction with betaadrenergic receptors of the plasma membrane and the launch of a cascade of reactions in the cell leading to the decomposition of glycogen and fats (Earl Sutherland, the Nobel Prize). Norepinephrine is more of a neurotransmitter than a hormone: the main site of synthesis – neurons of central nerve system (CNS). Biological effects of epinephrine (norepinephrine): 1) contraction of smooth muscle of vessels and increase of arterial pressure, increase of frequency and force of heart contractions, contraction of smooth muscles of other organs; 2) Mobilization of glucose and hyperglycemia (stimulates decomposition and inhibits the synthesis of glycogen); 3) Mobilization of fats (stimulates the decomposition of triglycerides, increases 4 the content of fatty acids in the blood); Principles of hormone action – A [4] The group of hydrophilic hormones consists of hormones derived from amino acids, as well as peptide hormones and proteohormones. Their receptors are located in the plasma membrane. Binding of the hormone to this type of receptor triggers a signal that is transmitted to the interior of the cell, where it controls the processes that allow the hormone signal to take effect (signal transduction). 5 Principles of hormone action – B [4] Lipophilic hormones, which include the steroid hormones, thyroxine, and retinoic acid, bind to a specific receptor protein inside their target cells. The complex formed by the hormone and the receptor then influences transcription of specific genes in the cell nucleus 6 [4] B Hormonal regulation of glucose metabolism in the liver A A 7 Regulation of lipolysis Hormones (that affect lipolytic processes) are divided into 2 groups: 1. Hormones of direct action (adrenaline, glucagon, somatotropin, insulin) 2. Hormones of mediated action (thyroid hormones, glucocorticoids, sex hormones, leptin) Epinephrine, glucagon, somatotropin, sex hormones, thyroxin and triiodothyronine, leptin stimulate lipolysis in adipocytes, and insulin is suppressed. 8 Classification of hormones I. According to chemical nature II. According to place of synthesis III. According to biological effect (true hormones and hormone like substances) IV. According to nature of action : starting hormones and hormones-performers (or hormones-players) V. According to mechanism of effect, there are 2 types: 1) action on receptor of external membrane of target cell; 2) action on receptors inside of cell 9 I – according to chemical nature, hormones are ➢protein-peptide nature hormones: protein (insulin), peptides (oxytocine); ➢derivatives of amino acids (thyroxine); ➢lipid-hormones: steroids (androsterone), eicosanoids; ➢derivatives of phenols (epinephrine or adrenaline) II – according to place of synthesis, hormones are divided into: ✓Hormones central endocrine structures ✓Hormones peripheral endocrine structures ✓Hormones of the mixed function ✓Hormones diffuse endocrine system 10 III – according to biological effect, hormones are: true hormones hormone like substances (hormoides) According to biological effect, hormones are: true hormones: 1) hormones of the hypothalamus (8 liberin or releasing factors and 3 statins, such as thyrotropin-releasing hormone (TRH), also called thyrotropin-releasing factor (TRF), thyroliberin or protirelin, gonadotropin-releasing hormone (GnRH), also known as luteinizing-hormone-releasing hormone (LHRH) and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, and somatostatin), pituitary hormones (anterior pituitary hormones or ‘adenohypophiz’: somatotropin, prolactin, folitropin, lutropin, corticotropin, thyrotropin; pituitary hormones secondary: melanotropin; posterior pituitary hormones secondary or ‘neurohypophiz’: vasopressin and oxytocin), pineal gland hormone (melanotonin); 11 2) thyroid hormones (such as triiodothyronine, calcitocin («гіпокальціємiйний гормон кальцитоцин»); 3) parathyroid gland hormones or parthyroid hormones (parathormone or parathyrin); 4) hormones of the adrenal gland (glucocorticoids – corticosteron, hydrocorticosteron, cortisone, mineralocorticoids – aldosterone, dezoxycorticosteron; androgens androstenedione, testosterone, estrogen – ‘estrogen ekvilenin’); 5) hormones of the adrenal hormones brain (catecholamines – adrenaline, noradrenaline); 6) hormones islet apparatus of the pancreas (insulin, glucagon, ‘lipokayin’, vahotonin; 7) hormones of male and female gonads (androgens: androsterone, dehidroandrosteron, testosterone, metyltestosteron; estrogens – estrone, estradiol, estratriol; gestagens – pregnan, progesterone, relaxin, androgens, hormones placenta – chorionic gonadotropin). 12 hormone like substances (hormonoids): ✓prostaglandins; ✓hormonoids gastrointestinal tract - gastrin, secretin, pancreozymin, cholecystokinin; ✓other hormonoids angiotensin, kinin; parahormone; ✓tissue hormone; ✓histo-hormone (histamine); ✓local action hormones; ✓neurohormones histamine, serotonin, acetylcholine. 13 IV – according to nature of action : starting hormones and hormonesperformers (or hormonesplayers) Starting hormone are hypothalamic neurohormones that stimulate the activities of the endocrine glands. Hormonesperformers are influenced on the main metabolic reactions of the organism that ensure its growth, development, production, adaptation, reproduction, various functional activities, etc. Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme 14 V – according to mechanism of effect, there are 2 types: 1) action on receptor of external membrane of target cell; 2) action on receptors inside of cell 1) effect on the outer membrane receptor target cells (protein and peptide hormones, catecholamine and horminoids) Hormone acts on the outer membrane receptor target cells, in which more is curried out → neurotransmitters (cAMP, cGMP, prostaglandin, Ca2+) → enzymes’ systems of target cells → metabolism in target cells 2) action on receptors within target cells (steroids, part of thyroid hormones) Hormone → inside target cells → interacts with molecules glycoprotein receptors localized in the cytosol, mitochondria and nuclear membrane → impact on the entire cellular metabolism, primarily on the processes of transcription in target cells 15 Insulin is composed of two peptide chains referred to as the A chain and B chain. A and B chains are linked together by two disulfide bonds, and an additional disulfide is formed within the A chain. In most species, the A chain consists of 21 amino acids and the B chain of 30 amino acids Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme 16 Insulin biosynthesis [4] Insulin is produced by the B cells of the islets of Langerhans in the pancreas. As is usualwith secretory proteins, the hormone’s precursor (preproinsulin) carries a signal peptide that directs the peptide chain to the interior of the endoplasmic reticulum. Proinsulin is produced in the ER by cleavage of the signal peptide and formation of disulfide bonds. Proinsulin passes to the Golgi apparatus, where it is packed into vesicles—the β-granules. After cleavage of the C peptide, mature insulin is formed in the β-granules and is stored in the form of zinc-containing hexamers until secretion. 17 Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale. 18 Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1), which starts many protein activation cascades (2). These include translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty 19 acid synthesis (6). Effects of insulin deficiency [4] Diabetes mellitus is a very common metabolic disease that is caused by absolute or relative insulin deficiency. The lack of this peptide hormone mainly affects carbohydrate and lipid metabolism. Diabetes mellitus occurs in two forms. In type 1 diabetes (insulindependent diabetes mellitus, IDDM), the insulin-forming cells are destroyed in young individuals by an autoimmune reaction. The less severe type 2 diabetes (noninsulindependent diabetes mellitus, NIDDM) usually has its first onset in elderly individuals. The causes have not yet been explained in detail in this type. 20 Carbohydrate metabolism regulation Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme 21 Structure Glucagon is a 29amino acid polypeptide. Its primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-PheThr-Ser-Asp-Tyr-Ser-Lys-TyrLeu-Asp-Ser-Arg-Arg-Ala-GlnAsp-Phe-Val-Gln-Trp-Leu-MetAsn-Thr-COOH. The polypeptide has a molecular weight of 3485 daltons. Glucagon is a peptide (nonsteroid) hormone. 22 Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme 23 Hormones Koolman, Color Atlas of Biochemist ry, 2nd edition © 2005 Thieme 24 Calcitriol and parathyroid hormone, on the one hand, and calcitonin on the other, ensure a more or less constant level of Ca2+ in theblood plasma and in the extracellular space (80– 110 mg 2.0–2.6 mM). The peptide parathyroid hormone (PTH; 84 AA) and the steroid calcitriol promote direct or indirect processes that raise the Ca2+ level in blood. Calcitriol increases Ca2+ resorption in the intestines and kidneys by inducing transporters. Parathyroid hormone supports these processes by stimulating calcitriol biosynthesis in the kidneys. In addition, it directly promotes resorption of Ca2+ in the kidneys and Ca2+ release from bone. The PTH antagonist calcitonin (32 AA) counteracts these processes. 25 Koolman, Color Atlas of Biochemistr y, 2nd edition © 2005 Thieme 26 Digestive hormones HCl secretion is stimulated by the peptide hormone gastrin, the mediator histamine, and - via the neurotransmitter acetylcholine - by the autonomous nervous system. The peptide somatostatin and certain prostaglandins have inhibitory effects. Together with cholecystokinin, secretin, and other peptides, gastrin belongs to the group of gastrointestinal hormones. All of these are formed in the gastrointestinal tract andmainly act in the vicinity of the site where they are formed - i.e., they are paracrine hormones. While gastrin primarily enhances HCl secretion, cholecystokinin and secretin mainly stimulate pancreatic 27 secretion and bile release. Адаптовано за Кольман Я., Рем К.-Г. Наглядная биохимия, 2009. 28 A. Renal hormones In addition to their involvement in excretion and metabolism, the kidneys also have endocrine functions. They produce the hormones erythropoietin and calcitriol and play a decisive part in producing the hormone angiotensin II by releasing the enzyme renin. Renal prostaglandins have a local effect on Na+ resorption. 29 Цитовано за Кольман Я., Рем К.-Г. Наглядная биохимия, 2009. 30 B. Renin–angiotensin system [4] The peptide hormone angiotensin II is not synthesized in a hormonal gland, but in the blood. The kidneys take part in this process by releasing the enzyme renin. Renin is an aspartate proteinase. It is formed by the kidneys as a precursor (prorenin), which is proteolytically activated into renin and released into the blood. In the blood plasma, renin acts on angiotensinogen, a plasma glycoprotein in the α2-globulin group (see p. 276), which like almost all plasma proteins is synthesized in the liver. The decapeptide cleaved off by renin is called angiotensin I. Further cleavage by peptidyl dipeptidase A (angiotensin-converting enzyme, ACE), a membrane enzyme located on the vascular endothelium in the lungs and other tissues, gives rise to the octapeptide angiotensin II, which acts as a hormone and neurotransmitter. The lifespan of angiotensin II in the plasma is only a few minutes, as it is rapidly broken down by other peptidases (angiotensinases), which occur in many different tissues. 31 Цитовано: Кольман Я., Рем К.-Г. Наглядная биохимия, 2009. 32