The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Edmund Maser - One of the best experts on this subject based on the ideXlab platform.
-
Hydroxysteroid Dehydrogenases hsds in bacteria a bioinformatic perspective
The Journal of Steroid Biochemistry and Molecular Biology, 2012Co-Authors: Michael Kisiela, Adam Skarka, Bettina Ebert, Edmund MaserAbstract:Steroidal compounds including cholesterol, bile acids and steroid hormones play a central role in various physiological processes such as cell signaling, growth, reproduction, and energy homeostasis. Hydroxysteroid Dehydrogenases (HSDs), which belong to the superfamily of short-chain Dehydrogenases/reductases (SDR) or aldo-keto reductases (AKR), are important enzymes involved in the steroid hormone metabolism. HSDs function as an enzymatic switch that controls the access of receptor-active steroids to nuclear hormone receptors and thereby mediate a fine-tuning of the steroid response. The aim of this study was the identification of classified functional HSDs and the bioinformatic annotation of these proteins in all complete sequenced bacterial genomes followed by a phylogenetic analysis. For the bioinformatic annotation we constructed specific hidden Markov models in an iterative approach to provide a reliable identification for the specific catalytic groups of HSDs. Here, we show a detailed phylogenetic analysis of 3 alpha-, 7 alpha-, 12 alpha-HSDs and two further functional related enzymes (3-ketosteroid-Delta(1)-dehydrogenase, 3-ketosteroid-Delta(4)(5 alpha)-dehydrogenase) from the superfamily of SDRs. For some bacteria that have been previously reported to posses a specific HSD activity, we could annotate the corresponding HSD protein. The dominating phyla that were identified to express HSDs were that of Actinobacteria, Proteobacteria, and Firmicutes. Moreover, some evolutionarily more ancient microorganisms (e.g., Cyanobacteria and Euryachaeota) were found as well. A large number of HSD-expressing bacteria constitute the normal human gastro-intestinal flora. Another group of bacteria were originally isolated from natural habitats like seawater, soil, marine and permafrost sediments. These bacteria include polycyclic aromatic hydrocarbons-degrading species such as Pseudomonas, Burkholderia and Rhodococcus. In conclusion, HSDs are found in a wide variety of microorganisms including bacteria and archaea, suggesting that steroid metabolism is an evolutionarily conserved mechanism that might serve different functions such as nutrient supply and signaling. Article from a special issue on steroids and microorganisms. (C) 2011 Elsevier Ltd. All rights reserved.
-
carbonyl reductases and pluripotent Hydroxysteroid Dehydrogenases of the short chain dehydrogenase reductase superfamily
Drug Metabolism Reviews, 2007Co-Authors: Frank Hoffmann, Edmund MaserAbstract:Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain Dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent Hydroxysteroid Dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.
-
Carbonyl reductases and pluripotent Hydroxysteroid Dehydrogenases of the short-chain dehydrogenase/reductase superfamily.
Drug metabolism reviews, 2007Co-Authors: Frank Hoffmann, Edmund MaserAbstract:Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain Dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent Hydroxysteroid Dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.
Jerzy Adamski - One of the best experts on this subject based on the ideXlab platform.
-
integrated view on 17beta Hydroxysteroid Dehydrogenases
Molecular and Cellular Endocrinology, 2009Co-Authors: Gabriele Moeller, Jerzy AdamskiAbstract:17beta-Hydroxysteroid Dehydrogenases (17beta-HSDs) are important enzymes in steroid metabolism. Long known members of the protein family seemed to be well characterised concerning their role in the regulation of the biological potency of steroid hormones, but today more and more evidence points to pivotal contributions of these enzymes in a variety of other metabolic pathways. Therefore, studies on 17beta-HSDs develop towards metabolomic survey. Latest research results give new insights into the complex metabolic interconnectivity of the 17beta-HSDs. In this paper metabolic activities of 17beta-HSDs will be compared, their interplay with endogenous substrates summarised, and interlacing pathways depicted. Strategies on deciphering the physiological role of 17beta-HSDs and the genetic predisposition for associated diseases will be presented.
-
recent advances in 17beta Hydroxysteroid Dehydrogenases
The Journal of Steroid Biochemistry and Molecular Biology, 2009Co-Authors: Cornelia Prehn, Gabriele Moller, Jerzy AdamskiAbstract:The metabolism of steroids at position 17 is catalysed by a growing number of 17beta-Hydroxysteroid Dehydrogenases (17β-HSDs). Several human diseases like breast or prostate cancer, endometriosis, metabolic syndrome and mental diseases were associated with dysfunctions of 17β-HSDs, which consequently became drug targets. This review will focus on identities of 17β-HSDs and recent advances in analyses of their physiological roles in steroid and lipid metabolism. It will also address the potential of metabolomics in drug development.
-
perspectives in understanding the role of human 17β Hydroxysteroid Dehydrogenases in health and disease
Annals of the New York Academy of Sciences, 2009Co-Authors: Marc Meier, Gabriele Moller, Jerzy AdamskiAbstract:Steroid signaling involves specific receptors that mediate genomic effects and many further proteins responsible for fast nongenomic activities. Metabolism at the position 17 of the steroid scaffold plays a pivotal role in the final regulation of the biological potency of steroid hormones. Enzymes responsible for that, the 17beta-Hydroxysteroid Dehydrogenases (17beta-HSD), act as carbonyl reductases and require cofactors for their catalytic activity. There is a substantial amount of evidence that human 17beta-HSDs are as well involved in the metabolic pathways of retinoids and fatty acid beyond that which has so far been anticipated. At present fourteen 17beta-HSDs have been annotated and characterized, and more might follow. Many of 17beta-HSDs have been shown to be involved in the pathogenesis of human disorders and are targets for therapeutic intervention. Strategies on deciphering the physiological role of the 17beta-HSD and the genetic predisposition for associated diseases will be presented involving analyses of animal models.
-
multifunctionality of human 17β Hydroxysteroid Dehydrogenases
Molecular and Cellular Endocrinology, 2006Co-Authors: Gabriele Moeller, Jerzy AdamskiAbstract:17β-Hydroxysteroid Dehydrogenases (17β-HSDs) belong to the family of short chain Dehydrogenases/reductases (SDRs) and aldoketo-reductases (AKRs). Some of the enzymes were discovered and named due to their enzymatic activity on steroid substrates or according to their sequence homology to other 17β-HSDs. During characterisation of these enzymes it turned out that their substrate specificity is broader than first expected and key functions of some 17β-HSDs in vivo are probably not in steroid metabolism but in basic metabolic pathways. The issue of such multifunctionality is the topic of this review.
-
inhibition of 17beta Hydroxysteroid Dehydrogenases by phytoestrogens comparison with other steroid metabolizing enzymes
The Journal of Steroid Biochemistry and Molecular Biology, 2005Co-Authors: Dominga Deluca, Gabriele Moller, Cornelia Prehn, Antje Krazeisen, Rainer Breitling, Jerzy AdamskiAbstract:Effects of phytoestrogens on human health have been reported for decades. These include not only beneficial action in cancer prevention but also endocrine disruption in males. Since then many molecular mechanisms underlying these effects have been identified. Targets of phytoestrogens comprise steroid receptors, steroid metabolising enzymes, elements of signal transduction and apoptosis pathways, and even the DNA processing machinery. Understanding the specific versus pleiotropic effects of selected phytoestrogens will be crucial for their biomedical application. This review will concentrate on the influence of phytoestrogens on 17beta-Hydroxysteroid Dehydrogenases from a comparative perspective with other steroid metabolizing enzymes.
Jonathan R. Seckl - One of the best experts on this subject based on the ideXlab platform.
-
11β Hydroxysteroid Dehydrogenases and the brain from zero to hero a decade of progress
Frontiers in Neuroendocrinology, 2011Co-Authors: Caitlin S Wyrwoll, Megan C Holmes, Jonathan R. SecklAbstract:Glucocorticoids have profound effects on brain development and adult CNS function. Excess or insufficient glucocorticoids cause myriad abnormalities from development to ageing. The actions of glucocorticoids within cells are determined not only by blood steroid levels and target cell receptor density, but also by intracellular metabolism by 11β-Hydroxysteroid Dehydrogenases (11β-HSD). 11β-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives and is widely expressed throughout the adult CNS. Elevated hippocampal and neocortical 11β-HSD1 is observed with ageing and causes cognitive decline; its deficiency prevents the emergence of cognitive defects with age. Conversely, 11β-HSD2 is a dehydrogenase, inactivating glucocorticoids. The major central effects of 11β-HSD2 occur in development, as expression of 11β-HSD2 is high in fetal brain and placenta. Deficient feto-placental 11β-HSD2 results in a life-long phenotype of anxiety and cardiometabolic disorders, consistent with early life glucocorticoid programming.
-
the role of 11β Hydroxysteroid Dehydrogenases in the brain
Molecular and Cellular Endocrinology, 2006Co-Authors: Megan C Holmes, Jonathan R. SecklAbstract:Abstract Glucocorticoids have a plethora of effects within the body to maintain homeostasis. In the brain they modify learning, memory and fear behaviours as well as regulating their own secretion by a negative feedback action. 11β-Hydroxysteroid Dehydrogenases (11β-HSDs) are glucocorticoid metabolising enzymes that modify actions of glucocorticoids in a tissue specific manner. 11β-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives, hence boosting tissue levels of corticosterone and cortisol. Removal of this enzyme (11β-HSD1−/− mice) results in apparent lower intra-hippocampal corticosterone levels and reduces glucocorticoid-associated cognitive decline during ageing. This low corticosterone tissue environment is maintained even though there is a hyperactive hypothalamic-pituitary-adrenal axis and elevated basal and stress-induced plasma corticosterone levels. Conversely, the major central effects of 11β-HSD2 are seen in development, as expression of 11β-HSD2 is high in fetal and certain parts of the neonate brain, but is confined to a few discrete regions of the adult brain. 11β-HSD2 acts as a dehydrogenase, inactivating corticosterone or cortisol through conversion to 11-dehydrocorticosterone and cortisone. Loss of 11β-HSD2 from the fetus and fetally derived tissues results in altered development of the cerebellum in the neonatal period and a life-long phenotype of anxiety, consistent with early life glucocorticoid programming.
-
The role of 11beta-Hydroxysteroid Dehydrogenases in the brain.
Molecular and cellular endocrinology, 2006Co-Authors: Megan C Holmes, Jonathan R. SecklAbstract:Glucocorticoids have a plethora of effects within the body to maintain homeostasis. In the brain they modify learning, memory and fear behaviours as well as regulating their own secretion by a negative feedback action. 11Beta-Hydroxysteroid Dehydrogenases (11beta-HSDs) are glucocorticoid metabolising enzymes that modify actions of glucocorticoids in a tissue specific manner. 11Beta-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives, hence boosting tissue levels of corticosterone and cortisol. Removal of this enzyme (11beta-HSD1-/- mice) results in apparent lower intra-hippocampal corticosterone levels and reduces glucocorticoid-associated cognitive decline during ageing. This low corticosterone tissue environment is maintained even though there is a hyperactive hypothalamic-pituitary-adrenal axis and elevated basal and stress-induced plasma corticosterone levels. Conversely, the major central effects of 11beta-HSD2 are seen in development, as expression of 11beta-HSD2 is high in fetal and certain parts of the neonate brain, but is confined to a few discrete regions of the adult brain. 11Beta-HSD2 acts as a dehydrogenase, inactivating corticosterone or cortisol through conversion to 11-dehydrocorticosterone and cortisone. Loss of 11beta-HSD2 from the fetus and fetally derived tissues results in altered development of the cerebellum in the neonatal period and a life-long phenotype of anxiety, consistent with early life glucocorticoid programming.
-
Genetic manipulation of 11β-Hydroxysteroid Dehydrogenases in mice
American journal of physiology. Regulatory integrative and comparative physiology, 2005Co-Authors: Janice M. Paterson, Jonathan R. Seckl, John J. MullinsAbstract:11β-Hydroxysteroid Dehydrogenases (HSDs) interconvert active 11-hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11-keto derivatives (cortisone, 11-dehydrocorticosterone). 11β-HSD...
-
11β Hydroxysteroid Dehydrogenases changing glucocorticoid action
Current Opinion in Pharmacology, 2004Co-Authors: Jonathan R. SecklAbstract:11β-Hydroxysteroid Dehydrogenases (11β-HSDs) catalyse the interconversion of active cortisol and inert cortisone. Two isozymes have been discovered, each with unique properties and powerful biological roles. 11β-HSD2 potently inactivates cortisol, protecting key tissues. By contrast, 11β-HSD1 regenerates cortisol, amplifying its actions in liver, fat and brain. Overexpression of this isozyme may contribute to the pathogenesis of the metabolic syndrome. Its inhibition is a potential therapeutic target for both metabolic and glucocorticoid-associated CNS disorders.
T M Penning - One of the best experts on this subject based on the ideXlab platform.
-
human Hydroxysteroid Dehydrogenases and pre receptor regulation insights into inhibitor design and evaluation
The Journal of Steroid Biochemistry and Molecular Biology, 2011Co-Authors: T M PenningAbstract:Abstract Hydroxysteroid Dehydrogenases (HSDs) represent a major class of NAD(P)(H) dependent steroid hormone oxidoreductases involved in the pre-receptor regulation of hormone action. This is achieved by HSDs working in pairs so that they can interconvert ketosteroids with Hydroxysteroids resulting in a change in ligand potency for nuclear receptors. HSDs belong to two protein superfamilies the aldo–keto reductases and the short-chain dehydrogenase/reductases. In humans, many of the important enzymes have been thoroughly characterized including the elucidation of their three-dimensional structures. Because these enzymes play fundamental roles in steroid hormone action they can be considered to be drug targets for a variety of steroid driven diseases, e.g. metabolic syndrome and obesity, inflammation, and hormone dependent malignancies of the endometrium, prostate and breast. This article will review how fundamental knowledge of these enzymes can be exploited in the development of isoform specific HSD inhibitors from both protein superfamilies. Article from the Special issue on Targeted Inhibitors.
-
structure function relationships in 3α Hydroxysteroid Dehydrogenases a comparison of the rat and human isoforms
The Journal of Steroid Biochemistry and Molecular Biology, 2003Co-Authors: T M Penning, Yi Jin, Vladi V Heredia, Mitchell LewisAbstract:Abstract 3α-Hydroxysteroid Dehydrogenases (3α-HSDs) inactivate steroid hormones in the liver, regulate 5α-dihydrotestosterone (5α-DHT) levels in the prostate, and form the neurosteroid, allopregnanolone in the CNS. Four human 3α-HSD isoforms exist and correspond to AKR1C1–AKR1C4 of the aldo-keto reductase (AKR) superfamily. Unlike the related rat 3α-HSD (AKR1C9) which is positional and stereospecific, the human enzymes display varying ratios of 3-, 17-, and 20-ketosteroid reductase activity as well as 3α-, 17β-, and 20α-Hydroxysteroid oxidase activity. Their kcat values are 50–100-fold lower than that observed for AKR1C9. Based on their product profiles and discrete tissue localization, the human enzymes may regulate the levels of active androgens, estrogens, and progestins in target tissues. The X-ray crystal structures of AKR1C9 and AKR1C2 (human type 3 3α-HSD, bile acid binding protein and peripheral 3α-HSD) reveal that the AKR1C2 structure can bind steroids backwards (D-ring in the A-ring position) and upside down (β-face inverted) relative to the position of a 3-ketosteroid in AKR1C9 and this may account for its functional plasticity. Stopped-flow studies on both enzymes indicate that the conformational changes associated with binding cofactor (the first ligand) are slow; they are similar in both enzymes but are not rate-determining. Instead the low kcat seen in AKR1C2 (50-fold less than AKR1C9) may be due to substrate “wobble” at the plastic active site.
-
Hydroxysteroid Dehydrogenases and pre receptor regulation of steroid hormone action
Human Reproduction Update, 2003Co-Authors: T M PenningAbstract:Steroid target tissues regulate the local level of steroid hormone that can bind and trans-activate nuclear receptors (a process known as intracrine modulation). This pre-receptor regulation can be achieved by Hydroxysteroid Dehydrogenases (HSDs). For each sex hormone there is a pair of HSD isoforms which act either as reductases or oxidases to convert potent steroid hormones into their cognate inactive metabolites, or vice-versa. In this manner, HSDs can function as molecular switches to regulate steroid hormone action. Because these HSDs show tissue-specific expression, inhibitors of these enzymes are predicted to cause tissue-specific responses to steroid hormones. These inhibitors would represent a new class of therapeutics called 'selective intracrine modulators' (SIMs). SIMs are expected to have the same tissue-specific effects as selective steroid receptor modulators but a different mode of action as their effects are enzyme- and not receptor-mediated. HSDs responsible for these interconversions belong to two protein superfamilies: the short-chain Dehydrogenases/reductases; and the aldo-keto reductases. Crystal structures exist for HSDs in both families, making rational design of SIMs a reality. Broad-based criteria have been established which must be fulfilled to validate each HSD isoform as a potential SIM target.
-
molecular endocrinology of Hydroxysteroid Dehydrogenases
Endocrine Reviews, 1997Co-Authors: T M PenningAbstract:I. Introduction II. 3β-Hydroxysteroid Dehydrogenase/Ketosteroid Isomerase (3β-HSD/KSI) A. Physiological and pharmacological significance B. Cloning and expression of the 3β-HSD/KSI cDNAs C. Structure, regulation, and tissue-specific expression of the 3β-HSD/KSI genes D. 3β-HSD deficiencies III. 17β-Hydroxysteroid Dehydrogenases A. Physiological and pharmacological significance B. Cloning and expression of the 17β-HSD cDNAs C. Structure, regulation, and tissue-specific expression of the 17β-HSD genes D. 17β-HSD deficiency IV. 11β-Hydroxysteroid Dehydrogenases A. Physiological and pharmacological significance B. Cloning and expression of the 11β-HSD cDNAs C. Structure, regulation, and tissue-specific expression of the 11β-HSD genes D. 11β-HSD deficiency V. 3α-Hydroxysteroid Dehydrogenases A. Physiological and pharmacological significance B. Cloning and expression of the 3α-HSD cDNAs C. Structure, regulation, and tissue-specific expression of the 3α-HSD genes D. 3α-HSD deficiencies VI. 20α-Hydroxysteroid Deh...
-
mammalian 3α Hydroxysteroid Dehydrogenases
Steroids, 1996Co-Authors: T M Penning, John E Pawlowski, Brian P Schlegel, Joseph M Jez, Hseuh Kung Lin, Susan S Hoog, Melanie J Bennett, Mitchell LewisAbstract:Abstract Mammalian 3α-Hydroxysteroid Dehydrogenases (3α-HSDs) regulate steroid hormone levels. For example, hepatic 3α-HSDs inactivate circulating androgens, progestins, and glucocorticoids. In target tissues they regulate access of steroid hormones to steroid hormone receptors. For example, in the prostate 3α-HSD acts as a molecular switch and controls the amount of 5α-dihydrotestosterone that can bind to the androgen receptor, while in the brain 3α-HSD can regulate the amount of tetrahydrosteroids that can alter GABA a receptor function. Molecular cloning indicates that these mammalian 3α-HSDs belong to the aldo-keto reductase superfamily and that they are highly homologous proteins. Using the three-dimensional structure of rat liver 3α-HSD as a template for site-directed mutagenesis, details regarding structure-function relationships, including catalysis and cofactor and steroid hormone recognition have been elucidated. These details may be relevant to all mammalian 3α-HSDs.
Frank Hoffmann - One of the best experts on this subject based on the ideXlab platform.
-
carbonyl reductases and pluripotent Hydroxysteroid Dehydrogenases of the short chain dehydrogenase reductase superfamily
Drug Metabolism Reviews, 2007Co-Authors: Frank Hoffmann, Edmund MaserAbstract:Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain Dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent Hydroxysteroid Dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.
-
Carbonyl reductases and pluripotent Hydroxysteroid Dehydrogenases of the short-chain dehydrogenase/reductase superfamily.
Drug metabolism reviews, 2007Co-Authors: Frank Hoffmann, Edmund MaserAbstract:Carbonyl reduction of aldehydes, ketones, and quinones to their corresponding hydroxy derivatives plays an important role in the phase I metabolism of many endogenous (biogenic aldehydes, steroids, prostaglandins, reactive lipid peroxidation products) and xenobiotic (pharmacologic drugs, carcinogens, toxicants) compounds. Carbonyl-reducing enzymes are grouped into two large protein superfamilies: the aldo-keto reductases (AKR) and the short-chain Dehydrogenases/reductases (SDR). Whereas aldehyde reductase and aldose reductase are AKRs, several forms of carbonyl reductase belong to the SDRs. In addition, there exist a variety of pluripotent Hydroxysteroid Dehydrogenases (HSDs) of both superfamilies that specifically catalyze the oxidoreduction at different positions of the steroid nucleus and also catalyze, rather nonspecifically, the reductive metabolism of a great number of nonsteroidal carbonyl compounds. The present review summarizes recent findings on carbonyl reductases and pluripotent HSDs of the SDR protein superfamily.