11β-Hydroxysteroid dehydrogenase

Class of enzymes 11β-Hydroxysteroid dehydrogenase (HSD-11β or 11β-HSD) enzymes catalyze the conversion of inert 11 keto-products (e.g. cortisone) to active cortisol, or vice versa,1.1.1.146Seckl JR, Walker BR Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action Endocrinology 142 4 1371–6 April 2001 11250914 10.1210/en.142.4.1371 free thus regulating the access of glucocorticoids to the steroid receptors. 60% cortisol + NADP+ reversible H+ H+ cortisone + NADPH The human genome encodes two distinct HSD-11β isozymes (HSD-11β Type 1 and HSD-11β Type 2) on distinct genes. The dehydrogenase activity of a HSD-11β converts a 11beta-hydroxysteroid to the corresponding 11-oxosteroid by reducing NADP+ or NAD+. HSD-11βs are part of the larger class of oxidoreductases and HSD-11β Type 1 has oxidoreductase activity (the reverse of dehydrogenase activity). HSD-11βs participate in c21-steroid hormone metabolism and androgen and estrogen metabolism. Structural studies Several structures for HSD-11β Type 1 have been solved to date with various mutations and inhibitors. There are no known structures for HSD-11β Type 2. Function thumb|left|200px|class=skin-invert-image|Cortisol. Note the OH at the 11 position on ring C. (The other differences between the diagrams are not of consequence.) thumb|right|200px|class=skin-invert-image|Cortisone Cortisol, a glucocorticoid, binds the glucocorticoid receptor. However, because of its molecular similarity to aldosterone it also binds the mineralcorticoid receptor at higher concentrations. Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor; however, there is vastly more cortisol in circulation than aldosterone. To prevent overstimulation of the mineralocorticoid receptor by cortisol, HSD-11βs convert the biologically active cortisol to the inactive cortisone, which can no longer bind the mineralocorticoid receptor.Hall John E. Guyton and Hall textbook of medical physiology 2021 Michael E. Hall 978-0-323-59712-8 14th Philadelphia, PA Elsevier 958 1129099861 HSD-11β co-localizes with intracellular adrenal steroid receptors. Licorice, which contains glycyrrhizinic acid and enoxolone, can inhibit HSD-11β and lead to the apparent mineralocorticoid excess syndrome. Cortisol levels consequently rise, and cortisol binding to the mineralocorticoid receptor produces clinical signs and symptoms of hypokalemia, alkalosis and hypertension (i.e., mineralocorticoid excess). Isozymes In humans, there are two 11β-HSD isozymes: Stewart PM, Krozowski ZS 11 beta-Hydroxysteroid dehydrogenase Vitamins and Hormones 57 249–324 1999 10.1016/S0083-6729(08)60646-9 10232052 978-0-12-709857-9 Seckl JR 11beta-Hydroxysteroid dehydrogenase in the brain: a novel regulator of glucocorticoid action? Front Neuroendocrinol 18 1 49–99 January 1997 9000459 10.1006/frne.1996.0143 46477930 Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis The Journal of Clinical Endocrinology and Metabolism 94 8 2009 2692–2701 19470627 10.1210/jc.2009-0370 free EnzymeGeneCofactor DependenceExpressionReactions catalyzed HSD-11β Type 1HSD11B1 NADPH-dependent Highly expressed in key metabolic tissues including liver, adipose tissue, and the central nervous system. Reduces cortisone to cortisol. HSD-11β Type 2 HSD11B2 NAD+-dependent Expressed in aldosterone-selective tissues, including kidneys, liver, lungs, colon, salivary glands, HSD2 neurons and placenta. Oxidizes cortisol to cortisone. Clinical application HSD-11βs are enzymes involved in steroid hormone physiology. HSD-11β Type 1 is found in metabolic tissues targeted by glucocorticoids and converts cortisone to active cortisol.http://kaitlinlindsay.com/the-11-%CE%B2-hsd-system/ Kaitlin Lindsay: Medical & Scientific Illustration Lindsay Kaitlin kaitlinlindsay.com https://web.archive.org/web/20190422204937/http://kaitlinlindsay.com/the-11-%ce%b2-hsd-system/ 2019-04-22 HSD-11β Type 1 acts as a reductase producing active cortisol and the amplification of glucocorticoids. This enzyme is most abundant in the liver but can be found in most tissues in the body. HSD11B- Type 1 amplifies glucocorticoid concentrations in the liver and adipose tissue, glucocorticoid excess induces obesity with other features such as hypertension and diabetes mellitus.Hughes Katherine A Webster Scott P Walker Brian R 2008-03-25 11-Beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors in Type 2 diabetes mellitus and obesity Expert Opinion on Investigational Drugs en 17 4 481–496 10.1517/13543784.17.4.481 18363514 72573025 1354-3784 HSD-11β Type 2 is expressed by aldosterone-selective tissues and protects the mineralocorticoid receptor from activation by cortisol by converting it to cortisone using the enzyme 11-oxoreductase. HSD-11β Type 2 protects tissues from continuous activation by decreasing local cortisol levels and preventing 11-oxoreductase from activating. In tissues that do not express the mineralocorticoid receptor, such as the placenta and testis, it protects cells from the growth-inhibiting and/or pro-apoptotic effects of cortisol, particularly during embryonic development. Mutations in this gene cause the syndrome of apparent mineralocorticoid excess and hypertension.https://www.genecards.org/cgi-bin/carddisp.pl?gene=HSD11B2 HSD11B2 Gene www.greencards.org Since the main functions of HSD-11βs are for the regulation of glucocorticoids, the two isozymes are linked to various overstimulation or depletion of glucocorticosteroids that result in chemical imbalances in the human body. The effects of the enzyme as it relates to specific body functions and its associated disorders are listed below. Effect of Hyperlipidemia on 11β-hydroxysteroid-dehydrogenase Hyperlipidemia has a great effect on 11β-hydroxysteroid-dehydrogenase.Sieber-Ruckstuhl Nadja S. Zini Eric Osto Melanie Franchini Marco Boretti Felicitas S. Meli Marina L. Sigrist Brigitte Lutz Thomas A. Reusch Claudia E. November 2010 Effect of hyperlipidemia on 11β-hydroxysteroid-dehydrogenase, glucocorticoid receptor, and leptin expression in insulin-sensitive tissues of cats https://www.zora.uzh.ch/id/eprint/36137/2/Sieber-Ruckstuhl_Effect_of_hyperlipidemia_2010.pdf Domestic Animal Endocrinology 39 4 222–230 10.1016/j.domaniend.2010.06.003 20688460 0739-7240 2019-12-11 2018-07-19 https://web.archive.org/web/20180719083840/http://www.zora.uzh.ch/id/eprint/36137/2/Sieber-Ruckstuhl_Effect_of_hyperlipidemia_2010.pdf dead Glucocorticoid is dependent on glucocorticoid plasma concentration, cellular glucocorticoid receptor expression and the pre-receptor hormone metabolism that is catalyzed by 11β-HSD. There are two types of 11β-Hydroxysteroid dehydrogenases that control cortisol concentration: HSD-11β Type 1 and HSD-11β Type 2. HSD-11β Type 1 is responsible for converting cortisone to cortisol by acting as an oxo-reductase because it is NADP(H) dependent, while HSD-11β Type 2 inactivates cortisol to cortisone via NAD. 10-d hyperlipidemia increases the HSD-11β Type 1 expression in visceral and subcutaneous adipose tissues. Hyperlipidemia decreases HSD-11β Type 2 expression in the liver and adipose tissue. Hyperlipidemia has a great influence on HSD-11β Type 1 and HSD-11β Type 2. This demonstrates that there is likely a relationship between hyperlipidemia and cortisol metabolism. Cushing's Disease, synonymous with hypercortisolism, involves overwhelming the cortisol-neutralizing ability of 11β-HSD2 with high concentrations of cortisol.Cicala Maria Verena Mantero Franco 2010 Hypertension in Cushing's Syndrome: From Pathogenesis to Treatment https://www.karger.com/Article/FullText/314315 Neuroendocrinology en 92 Suppl. 1 44–49 10.1159/000314315 0028-3835 20829617 free This allows cortisol to outcompete aldosterone and bind to mineralocorticoid receptors, resulting in the activation of several pathways that increase blood pressure.Fuller Peter J. Young Morag J. 2005-12-01 Mechanisms of Mineralocorticoid Action Hypertension 46 6 1227–1235 10.1161/01.HYP.0000193502.77417.17 16286565 14749847 free Activity of HSD-11βs in organs HSD-11βs are active in organs and in the adrenal gland.Cherkasova O. P. Selyatitskaya V. G. Pal'chikova N. A. Kuznetsova N. V. 2014-11-29 Activity of 11β-Hydroxysteroid Dehydrogenase in the Adrenal Glands, Liver, and Kidneys of Rats with Experimental Diabetes Bulletin of Experimental Biology and Medicine en 158 2 185–187 10.1007/s10517-014-2718-3 25430643 24224772 0007-4888 The two isoenzymes take on various duties. During an active state, HSD-11β promotes the increase in glucocorticoids in the hepatocytes and also enhances gluconeogenesis. The type 2 isozyme converts active glucocorticoid hormones to inactive metabolites in target tissues such as kidney, salivary glands, intestines, etc. The activation of the two isozymes of HSD-11β in the kidneys and liver triggers the extra-adrenal formation in alloxan diabetes, which affiliates with the reduction in the synthesis of glucocorticoid hormones in the adrenal glands. The extra-adrenal formation leads to the increased local formation of corticosterone in the liver and has a high activity of reactions with gluconeogenesis. These gluconeogenesis reactions add to the continued metabolic disorders similar to that of diabetes. Thus, inhibitors of HSD-11β Type 1 are potential treatment agents for diabetes mellitus, obesity, and metabolic syndrome by decreasing production of active glucocorticoids. Involvement in the brain HSD-11βs are expressed in the central nervous system of aged individuals.Wyrwoll Caitlin S. Holmes Megan C. Seckl Jonathan R. August 2011 11β-Hydroxysteroid dehydrogenases and the brain: From zero to hero, a decade of progress Frontiers in Neuroendocrinology 32 3 265–286 10.1016/j.yfrne.2010.12.001 21144857 0091-3022 3149101 It is essential in Hypothalamo-Pituitary-Adrenal Axis function. HSD-11βs also partakes involvement in the decline of conscious intellectual activity due to aging. The enzyme also contributes to central effects are also during the development stages. For instance, the HSD-11βs Type 2 shows frequently in fetal tissues such as a newborn's brain and placenta. If there is an absence or decline in HSD-11βs Type 2 in the fetus tissues, there are negative developmental consequences such as anxiety. HSD-11βs are partly responsible for intracellular metabolism that determine the operation of glucocorticoids within cells. Glucocorticoids impact the brain development and ultimately the function of the central nervous system. So much so, that if there is a surplus or scant amounts of it, the consequences are deformities throughout one's entire life. HSD-11β Type 1 is responsible for activating glucocorticoids while HSD-11β Type 2 is responsible for deactivating them. The consequences for HSD-11β Type 1 activating glucocorticoids is that there is a decline in cognition especially as one ages. Contrarily, the effects of HSD-11β Type 2 occur during development. Some consequences of a high expression HSD-11β Type 2 are anxiety and cardiometabolic disorders, both of which are part of the early age glucocorticoid programming. Preterm birth Infants born underweight are susceptible to having metabolic disease throughout their lives.Rogers Samantha L. Hughes Beverly A. Jones Christopher A. Freedman Lauren Smart Katherine Taylor Norman Stewart Paul M. Shackleton Cedric H. L. Krone Nils P. May 2014 Diminished 11β-Hydroxysteroid Dehydrogenase Type 2 Activity Is Associated With Decreased Weight and Weight Gain Across the First Year of Life The Journal of Clinical Endocrinology & Metabolism en 99 5 E821–E831 10.1210/jc.2013-3254 24517145 0021-972X free 2299/14902 free The presence of glucocorticoids has contributed to the relatively low infant birth weight. A decrease in HSD-11β Type 2 in the placenta can lead to infant restriction in growth, specifically during the first 12 months of an infant's life. The reason for this is because the HSD-11β Type 2 is meant to be expressed in high quantities in the placenta, This is so because the enzymes secure the fetus from exposure to increased levels of glucocorticoids, which are linked to underweight newborns. See also Steroidogenic enzyme 11β-Hydroxysteroid dehydrogenase type 1 11β-Hydroxysteroid dehydrogenase type 2 Cortisone reductase deficiency References Agarwal AK, Monder C, Eckstein B, White PC 1989 Cloning and expression of rat cDNA encoding corticosteroid 11 beta-dehydrogenase J. Biol. Chem. 264 18939–43 2808402 32 10.1016/S0021-9258(19)47248-7 free Bush IE, Hunter SA, Meigs RA 1968 Metabolism of 11-oxygenated steroids. Metabolism in vitro by preparations of liver Biochem. J. 107 239–58 4384445 2 1198650 10.1042/bj1070239 Lakshmi V, Monder C 1988 Purification and characterization of the corticosteroid 11 beta-dehydrogenase component of the rat liver 11 beta-hydroxysteroid dehydrogenase complex Endocrinology 123 2390–8 3139396 10.1210/endo-123-5-2390 5 Phillips DM, Lakshmi V, Monder C 1989 Corticosteroid 11 beta-dehydrogenase in rat testis Endocrinology 125 209–16 2661206 10.1210/endo-125-1-209 1 External links 11-beta-Hydroxysteroid+Dehydrogenases Biology no Category:EC 1.1.1 Category:NADPH-dependent enzymes Category:Enzymes of known structure