DOCSLIB.ORG

Co-Evolution of Steroidogenic and Steroid-Inactivating Enzymes and Adrenal and Sex Steroid Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Co-Evolution of Steroidogenic and Steroid-Inactivating Enzymes and Adrenal and Sex Steroid Receptors UC San Diego UC San Diego Previously Published Works Title Co-Evolution of Steroidogenic and Steroid-Inactivating Enzymes and Adrenal and Sex Steroid Receptors Permalink https://escholarship.org/uc/item/8f6111pm Journal Molecular and Cellular Endocrinology, 215 Author Baker, Michael E Publication Date 2004 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Molecular and Cellular Endocrinology Vol. 215, pp. 55 -62, 2004. Co-Evolution of Steroidogenic and Steroid-Inactivating Enzymes and Adrenal and Sex Steroid Receptors Michael E. Baker Department of Medicine, 0 69 3 University of California, San Diego 9500 Gilm an Drive La Jolla, CA 92093 -069 3 phone: 858 -858 -534, -8317; fax: 858 -822 -0873 e-mail: [email protected] Abstract . Receptors for the adrenal and sex steroids arose by a series of gene duplications from an ancestral nuc lear receptor in a primitive vertebrate , at least 540 million years ago . Sequence analysis indicates many steroidogenic and steroid -inactivating enzymes, including cytochrome P450s and hydroxysteroid dehydrogenases, arose at the same time. The estrogen r eceptor (ER) appears to be the ancestral steroid receptor. Initially, the r edundant duplicated ER had a low specificity for its new ligand . This raises the question: “How was specificity for responses to different steroids regulated early in the evolutio n of steroid receptors?” Selective expression of these steroid -metabolizing enzymes provide d specificity for different steroid responses in primitive vertebrates . 17 -hydroxysteroid dehydrogenase -type 1 ( 17 -HSD -type 1) and 17 -HSD -type 2, which preferen tially catalyze the reduction and oxidation at C17 of androgens and estrogens, respectively, provide an example of this mechanism. Selective expression of either 17 -HSD -type 1 or 17 -HSD -type 2 can regulate synthesis or inactivation of androgens or estro gens in specific cells. Steroids also w ere important in the evolution of land animals, which began about 400 million years ago. Steroid ogenic and steroid -inactivating enzymes were recruited to regulate steroid -mediated responses as organ function became more complex. For example , i n the kidney 11 -HSD -type 2 prevents binding of glucocorticoids to the mineralocorticoid receptor, which is crucial for aldosterone -mediated regulation of electrolyte t ransport in the distal tubule. We propose that 5 steroids, such as dehydroepiandrosterone and its met abolites, were the ligands for the ancestral ER. Understanding the actions of 5 steroids in amphioxus and lamprey may shed light on adrenarche and neurosteroid actions in humans. 1. Steroid receptors, steroidogenic enzymes and steroid -inactivating enzym es regulate steroid hormone action. The adrenal and sex steroids - aldosterone, cortisol, estradiol, progesterone and testosterone - regulate a wide range of physiological processes in vertebrates including reproduction , development and homeostasis. As a result, there has been much interest in understanding the mechanism of action of these hormones , and, in particular, how the receptors, which mediate their actions, regulate gene transcription . Although enzymes in steroidogenic tissues, such as adrenals, ovaries and testis, from where steroids were secreted into the circulatory system, were characterized, for the most part , s teroidogenic and steroid - inactivating enzymes were not at the center stage in endocrine research . However, research on steroidogeni c and steroid -inactivating enzymes increased, after it was realized that local expression of steroidogenic and steroid -inactivating enzymes has a key role in steroid hormone action (Funder et al., 1988; Edwards et al. , 1996) . Enzymes that metabolize a sin gle group , such as a hydroxyl or ketone, on steroid, can either activate or inactivate a steroid. This constitutes an economical on -off switch for regulating steroid hormone action because r eversible inactivation and activation of steroids as they circula te throu gh different organs conserves a complex molecule that req uire s over 25 steps for its synthesis. Selective expression in peripheral organs of enzymes that catalyze this on -off switch is a n essential part of paracrine, autocrine an intracrine mechan isms for regulating steroid responses (Labrie et al. , 2000) , which t ogether with the expression of steroid receptors in target tissues , provide a flexible mechanism for regulating diverse physiological responses vertebrates . As will be discussed in this a rticle, steroid receptors , steroidogenic enzymes and steroid -inactivating enzymes arose at about the same time in primitive vertebrates, and the subsequent co -evolution of these proteins was important in the evolution of complex developmental pathways foun d in vertebrates (Baker , 2003) . Moreover, understanding the early events in the evolution of steroidogenic enzymes may shed light on adrenarche (Arlt et al. 2002; Rainey et al., 2002) and the actions of neurosteroids (Baulieu and Robel, 1998; Compagnone a nd Mellon, 1998) in humans. 2. Adrenal and sex steroid receptors are a vertebrate innovation. Steroid receptors belong to the nuclear receptor family of transcription factors (Escriva et al. , 2000). Nuclear receptors are found in vertebrates and inverteb rates , but not in yeast or plants . Thus far, adrenal and sex steroid receptors have been found only in vertebrates (Baker, 2002 a, 2003 ). This is consistent with PCR analysis of DNA from phylogenetically diver se animals (Escriva et al. 1997) and sequence analysis steroid receptors (Baker, 1997, 200 1b, 2003 ; Escriva et al., 2000) , both of which conclude that adrenal and sex steroid receptors arose at the beginning of the vertebrate line . Recent work from lamprey , a jawless fish, and Ciona intestinalis , a ur ochordate, further narrows the timing of origins of adrenal and sex steroid receptors. Thornton (2001) found an ancestral estrogen receptor 2 (ER), progesterone receptor (PR) and corticoid receptor (CR) in the lamprey, a jawless fish. A n a nalysis of the re cently completed genome of Ciona indicates that this organism does not have receptors for adrenal and sex steroids (Dehal et al. 2002; Baker, 2003). Together these analyses suggest that adrenal and sex steroid receptors arose in a cephalochordate , such as amphioxus , or in a jawless fish [Figure 1] . No : ER, PR, GR, AR, MR C. elegans P450scc, P450c17, P450arom Protostomes D. melanogaster 3/4/5 -HSD, 11 -HSD -1,2, 17 -HSD -1,2 Echinoderms Urochordates Deuterostomes Ciona Cephalochordates Amphioxus Lamprey No : ER, PR, GR, AR, MR Sharks P450scc, P45 0c17, P450arom ER? 4/5 3/ -HSD, 11 -HSD -1,2 Ray -Finned Fish 17 -HSD -1,2 ER, PR, CR Land Vertebrates ER, PR, GR, AR, MR P450scc, P450c17, P450arom 3/4/5 -HSD, 11 -HSD -1,2, 17 -HSD -1,2 Figure 1. Adrenal and sex steroid signaling arose in a chordate. Bony fish contain adrenal and sex steroid receptors and steroidogenic and steroid -inactivating enzymes. BLAST search es of the genome of Ciona intestinalis with these mammalian and fish sequences reveals that Ciona lacks genes coding for adrenal and sex steroid receptors and many of the key enzymes necessary for steroid synthesis (Dehal et al. 2002; Baker 2003). This su ggests that the ancestral steroid receptor arose in a cephalochordate such as amphioxus (Baker, 1997, 2001b). 3. Several key s teroidogenic and steroid -inactivating enzymes arose at the origin of vertebrates. Figure 2 shows the cytochrome P450s and hydroxy steroid dehydrogenases that catalyze the synthesis of adrenal and sex stero id receptors from cholesterol (Nebert and Russell, 2002) . Metabolism of cholesterol to pregnenolone by cytochrome P450s cc is followed by co nversion of pregnenolone to progesterone by 5-4 5-4 3/ -hydroxysteroid dehydrogenase (3 / -HSD) . This yields an active steroid, which also is a precursor for the other adrenal and sex steroids. 3 Cholesterol CYP11A1 P450scc CYP21A1 CYP11B1 P450c21 P450c11 5-4 Pregnenolone 3/ HSD Progesterone Deoxycorticosterone Corticosterone CYP17A1 CYP17A1 CYP11B2 P450c17 P450c17 CYP21A1 P450aldo 5-4 3/ HSD P450c21 17 -OH -Pregnenolone 17 -OH -Progestero ne 11 -Deoxycortisol 18 -OH -Corticosterone CYP17A1 CYP11B1 CYP11B2 P450c17 P450c11 P450aldo 5-4 DHEA 3/ HSD Androstenedione Cortisol Aldosterone CYP1 9A1 17 -HSD P450arom Estrone Testosterone Figure 2. Enzymes involved in the synthesis of adrenal and sex steroids. Progesterone is metabolized by v arious cytochrome P450s to corticost erone, cortisol and aldosterone [F igure 2]. Interestingly, a ndrostenedione, a precursor of active androgens and estrogens, is formed dehydroepiandrostenedione (DHEA), a 5 steroid (Mille r, 2002). And rostenedione is aromatized to estrone by cytochrome P450 arom . 17 -hydroxysteroid dehydrogenase -type 1 (17 -HSD -type 1) and possibl y other 17 -HSDs ( Baker, 1996, 2001a; Peltoketo et al., 1999 ; Labrie et al., 2000 ) catalyze the formation of te stosterone from androstenedione and estradiol from estrone . Thus, a combination of cytochrome P450s and steroid dehydrogenases catalyze the conversion of cholesterol to a drenal and sex steroids. Other cytochrome P450s inactivate steroids by addition of hy droxyl groups, which facilitates steroid excretion and maintain s proper steroid concentrations . Some s teroid dehydrogenases inactivate steroids , as part of an on -off switch that is important in steroid homeostasis. Two important enzymes for this mechanis m are 11 -hydroxysteroid dehydrogenase -type 2 (11 -HSD -type 2) and 17 -HSD -type
Load more

Recommended publications
  • De Novo Sequencing and Transcriptome Analysis Reveal Key Genes Regulating Steroid Metabolism in Leaves, Roots, Adventitious Roots and Calli of Periploca Sepium Bunge
    ORIGINAL RESEARCH published: 21 April 2017 doi: 10.3389/fpls.2017.00594 De novo Sequencing and Transcriptome Analysis Reveal Key Genes Regulating Steroid Metabolism in Leaves, Roots, Adventitious Roots and Calli of Periploca sepium Bunge Jian Zhang 1, 2, 3, Xinglin Li 1, 3*, Fuping Lu 1, 3, Shanying Wang 1, 3, Yunhe An 4, Xiaoxing Su 4, Xiankuan Li 2, Lin Ma 2 and Guangjian Han 5 1 Key Lab of Industrial Fermentation Microbiology, Tianjin University of Science and Technology, Ministry of Education, Tianjin, China, 2 School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China, 3 College of Bioengineering, Tianjin University of Science and Technology, Tianjin, China, 4 Beijing Center for Physical and Chemical Analysis, Beijing, China, 5 Shachuan Biotechnology, Tianjin, China Edited by: Periploca sepium Bunge is a traditional medicinal plant, whose root bark is important Peng Zhang, Institute of Plant Physiology and for Chinese herbal medicine. Its major bioactive compounds are C21 steroids and Ecology, SIBS, CAS, China periplocin, a kind of cardiac glycoside, which are derived from the steroid synthesis Reviewed by: pathway. However, research on P. sepium genome or transcriptomes and their related Kun Yu, genes has been lacking for a long time. In this study we estimated this species Hubei University of Chinese Medicine, China nuclear genome size at 170 Mb (using flow cytometry). Then, RNA sequencing of Jun Yang, four different tissue samples of P. sepium (leaves, roots, adventitious roots, and Shanghai Chenshan Plant Science Research Center (CAS), China calli) was done using the sequencing platform Illumina/Solexa Hiseq 2,500.
    [Show full text]
  • Characterization of the Ergosterol Biosynthesis Pathway in Ceratocystidaceae
    Journal of Fungi Article Characterization of the Ergosterol Biosynthesis Pathway in Ceratocystidaceae Mohammad Sayari 1,2,*, Magrieta A. van der Nest 1,3, Emma T. Steenkamp 1, Saleh Rahimlou 4 , Almuth Hammerbacher 1 and Brenda D. Wingfield 1 1 Department of Biochemistry, Genetics and Microbiology, Forestry and Agricultural Biotechnology Institute (FABI), University of Pretoria, Pretoria 0002, South Africa; [email protected] (M.A.v.d.N.); [email protected] (E.T.S.); [email protected] (A.H.); brenda.wingfi[email protected] (B.D.W.) 2 Department of Plant Science, University of Manitoba, 222 Agriculture Building, Winnipeg, MB R3T 2N2, Canada 3 Biotechnology Platform, Agricultural Research Council (ARC), Onderstepoort Campus, Pretoria 0110, South Africa 4 Department of Mycology and Microbiology, University of Tartu, 14A Ravila, 50411 Tartu, Estonia; [email protected] * Correspondence: [email protected]; Fax: +1-204-474-7528 Abstract: Terpenes represent the biggest group of natural compounds on earth. This large class of organic hydrocarbons is distributed among all cellular organisms, including fungi. The different classes of terpenes produced by fungi are mono, sesqui, di- and triterpenes, although triterpene ergosterol is the main sterol identified in cell membranes of these organisms. The availability of genomic data from members in the Ceratocystidaceae enabled the detection and characterization of the genes encoding the enzymes in the mevalonate and ergosterol biosynthetic pathways. Using Citation: Sayari, M.; van der Nest, a bioinformatics approach, fungal orthologs of sterol biosynthesis genes in nine different species M.A.; Steenkamp, E.T.; Rahimlou, S.; of the Ceratocystidaceae were identified.
    [Show full text]
  • Effects on Steroid 5-Alpha Reductase Gene Expression of Thai Rice Bran Extracts and Molecular Dynamics Study on SRD5A2
    biology Article Effects on Steroid 5-Alpha Reductase Gene Expression of Thai Rice Bran Extracts and Molecular Dynamics Study on SRD5A2 Chiranan Khantham 1 , Wipawadee Yooin 1,2 , Korawan Sringarm 2,3 , Sarana Rose Sommano 2,4 , Supat Jiranusornkul 1, Francisco David Carmona 5,6 , Wutigri Nimlamool 7 , Pensak Jantrawut 1,2, Pornchai Rachtanapun 8,9 and Warintorn Ruksiriwanich 1,2,8,* 1 Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand; [email protected] (C.K.); [email protected] (W.Y.); [email protected] (S.J.); [email protected] (P.J.) 2 Cluster of Research and Development of Pharmaceutical and Natural Products Innovation for Human or Animal, Chiang Mai University, Chiang Mai 50200, Thailand; [email protected] (K.S.); [email protected] (S.R.S.) 3 Department of Animal and Aquatic Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai 50200, Thailand 4 Plant Bioactive Compound Laboratory (BAC), Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai 50200, Thailand 5 Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, 18071 Granada, Spain; [email protected] 6 Instituto de Investigación Biosanitaria ibs.GRANADA, 18014 Granada, Spain 7 Citation: Khantham, C.; Yooin, W.; Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Sringarm, K.; Sommano, S.R.; [email protected] 8 Cluster of Agro Bio-Circular-Green Industry, Faculty of Agro-Industry, Chiang Mai University, Jiranusornkul, S.; Carmona, F.D.; Chiang Mai 50100, Thailand; [email protected] Nimlamool, W.; Jantrawut, P.; 9 School of Agro-Industry, Faculty of Agro-Industry, Chiang Mai University, Chiang Mai 50100, Thailand Rachtanapun, P.; Ruksiriwanich, W.
    [Show full text]
  • Crystal Structure of Steroid Reductase SRD5A Reveals Conserved Steroid Reduction Mechanism
    ARTICLE https://doi.org/10.1038/s41467-020-20675-2 OPEN Crystal structure of steroid reductase SRD5A reveals conserved steroid reduction mechanism Yufei Han 1,9, Qian Zhuang2,9, Bo Sun3,9, Wenping Lv 4,9, Sheng Wang5,9, Qingjie Xiao6, Bin Pang1, ✉ Youli Zhou1, Fuxing Wang1, Pengliang Chi6, Qisheng Wang3, Zhen Li7, Lizhe Zhu 4, Fuping Li8, Dong Deng6 , ✉ ✉ ✉ Ying-Chih Chiang 1 , Zhenfei Li 2 & Ruobing Ren 1 Steroid hormones are essential in stress response, immune system regulation, and repro- 1234567890():,; duction in mammals. Steroids with 3-oxo-Δ4 structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A- mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A from Proteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical char- acterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ4 reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.
    [Show full text]
  • Late Diagnosis of 5Alpha Steroid-Reductase Deficiency Due to IVS12A>G Mutation of the Srd5a2 Gene in an Adolescent Girl Presented with Primary Amenorrhea
    HORMONES 2011, 10(3):230-235 Case Report Late diagnosis of 5alpha steroid-reductase deficiency due to IVS12A>G mutation of the SRD5a2 gene in an adolescent girl presented with primary amenorrhea Nicos Skordis,1,2 Christos Shammas,2 Elisavet Efstathiou,1 Amalia Sertedaki,3 Vassos Neocleous,2 Leonidas Phylactou2 1Pediatric Endocrine Unit, Makarios Hospital, Nicosia, Cyprus, 2Department of Molecular Genetics Function & Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 3Unit of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, Athens University, Medical School, Athens, Greece ABSTRACT BACKGROUND: The clinical spectrum of 5α-reductase deficiency, caused by mutations in the SRD5A2 gene, ranges from complete female appearance of the external genitalia at birth to nearly complete male phenotype. CASE REPORT: A 14-year-old girl presented with primary amenorrhea (PA) and lack of breast development. She was 173 cm in height, had an increased amount of pubic hair and clitoromegaly (3 cm), with a 4 cm blind vaginal pouch. Gonads were palpable in the inguinal canal bilaterally and no uterus was identified on ultrasound. C hromosomal analysis showed a 46,XY karyotype. The Testosterone/DHT ratio was high (16.5) and further increased to 29.4 after stimulation with hCG, thus favouring the diagnosis of 5α-reductase deficiency. Since the issue of gender change was not considered, gonadectomy was performed followed by successful feminisation with hormonal replacement therapy. GE- NETIC STUDIES: Molecular analysis of the SRD5A2 gene by DNA sequencing of all 5 exons revealed the presence of the splice mutation A>G at position -2 of the acceptor site of intron 1/exon 2 (IVS1-2A>G) in homozygosity.
    [Show full text]
  • Disruption of Androgen Metabolism, Regulation and Effects: Involvement of Steroidogenic Enzymes
    Disruption of Androgen Metabolism, Regulation and Effects: Involvement of Steroidogenic Enzymes Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Cornelia Fürstenberger, aus Basel, Schweiz Basel, 2014 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Alex Odermatt (Fakultätsverantwortlicher) ________________________ Fakultätsverantwortlicher Prof. Dr. Alex Odermatt und Prof. Dr. Rik Eggen (Korreferent) ________________________ Korreferent Prof. Dr. Rik Eggen Basel, den 20. Mai 2014 ________________________ Dekan Prof. Dr. Jörg Schibler 2 Table of content Table of content I. Abbreviations ................................................................................................................................. 6 1. Summary ........................................................................................................................................ 9 2. Introduction .................................................................................................................................. 12 2.1 Steroid hormones .................................................................................................................. 12 2.2 Steroidogenesis ..................................................................................................................... 14 2.3 Steroid hormones in health and disease ..............................................................................
    [Show full text]
  • Characterization of Precursor-Dependent Steroidogenesis in Human Prostate Cancer Models
    cancers Article Characterization of Precursor-Dependent Steroidogenesis in Human Prostate Cancer Models Subrata Deb 1 , Steven Pham 2, Dong-Sheng Ming 2, Mei Yieng Chin 2, Hans Adomat 2, Antonio Hurtado-Coll 2, Martin E. Gleave 2,3 and Emma S. Tomlinson Guns 2,3,* 1 Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] 2 The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC V6H 3Z6, Canada; [email protected] (S.P.); [email protected] (D.-S.M.); [email protected] (M.Y.C.); [email protected] (H.A.); [email protected] (A.H.-C.); [email protected] (M.E.G.) 3 Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V5Z 1M9, Canada * Correspondence: [email protected]; Tel.: +1-604-875-4818 Received: 14 August 2018; Accepted: 17 September 2018; Published: 20 September 2018 Abstract: Castration-resistant prostate tumors acquire the independent capacity to generate androgens by upregulating steroidogenic enzymes or using steroid precursors produced by the adrenal glands for continued growth and sustainability. The formation of steroids was measured by liquid chromatography-mass spectrometry in LNCaP and 22Rv1 prostate cancer cells, and in human prostate tissues, following incubation with steroid precursors (22-OH-cholesterol, pregnenolone, 17-OH-pregnenolone, progesterone, 17-OH-progesterone). Pregnenolone, progesterone, 17-OH-pregnenolone, and 17-OH-progesterone increased C21 steroid (5-pregnan-3,20-dione, 5-pregnan-3,17-diol-20-one, 5-pregnan-3-ol-20-one) formation in the backdoor pathway, and demonstrated a trend of stimulating dihydroepiandrosterone or its precursors in the backdoor pathway in LNCaP and 22Rv1 cells.
    [Show full text]
  • The Regulation and Membrane Topology of DHCR24, a Key Enzyme in Cholesterol Synthesis
    The regulation and membrane topology of DHCR24, a key enzyme in cholesterol synthesis by Eser J. Zerenturk A thesis submitted in fulfilment of the requirements for the Degree of Doctorate of Philosophy (Biochemistry and Molecular Genetics) School of Biotechnology and Biomolecular Sciences The University of New South Wales Submitted: December 2013 Revised: April 2014 THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Zerenturk First name: Eser Other name/s: Jane Abbreviation for degree as given in the University calendar: PhD School: Biotechnology and Biomolecular Sciences Faculty: Science Title: The regulation and membrane topology of DHCR24, a key enzyme in cholesterol synthesis Abstract 350 words maximum: Cholesterol is necessary for mammalian life, as an essential component in cell membranes, foetal development, and a precursor for steroid hormones. Hence, cholesterol levels must be tightly regulated. Previous research has focused on an early step in cholesterol synthesis: 3- hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), target of the cholesterol-lowering statin drugs. However, less is known about other steps in the pathway. We investigated 3β-hydroxysterol Δ24-reductase (DHCR24); involved in the last step of cholesterol synthesis, and implicated in inflammation, oxidative stress and hepatitis C virus infection. There is a paucity of fundamental information on the structure of DHCR24 and how it interacts with cellular membranes, as well as how this critical enzyme is regulated. We found that DHCR24 is an integral endoplasmic reticulum (ER) membrane protein, with multiple atypical membrane associated regions. We present biochemical evidence that the majority of the enzyme is associated with the ER membrane, contrary to published membrane topology models and in silico predictions.
    [Show full text]
  • REVIEW 5A-Reduced Glucocorticoids: a Story of Natural Selection
    111 REVIEW 5a-Reduced glucocorticoids: a story of natural selection Mark Nixon, Rita Upreti and Ruth Andrew Endocrinology, Queen’s Medical Research Institute, University/British Heart Foundation Centre for Cardiovascular Science, Edinburgh EH16 4TJ, UK (Correspondence should be addressed to R Andrew; Email: [email protected]) Abstract 5a-Reduced glucocorticoids (GCs) are formed when one of recently the abilities of 5a-reduced GCs to suppress the two isozymes of 5a-reductase reduces the D4–5 double inflammation have been demonstrated in vitro and in vivo. bond in the A-ring of GCs. These steroids are largely viewed Thus, the balance of parent GC and its 5a-reduced inert, despite the acceptance that other 5a-dihydro steroids, metabolite may critically affect the profile of GR signalling. e.g. 5a-dihydrotestosterone, retain or have increased activity 5a-Reduction of GCs is up-regulated in liver in metabolic at their cognate receptors. However, recent findings suggest disease and may represent a pathway that protects from both that 5a-reduced metabolites of corticosterone have dis- GC-induced fuel dyshomeostasis and concomitant inflam- sociated actions on GC receptors (GRs) in vivo and in vitro matory insult. Therefore, 5a-reduced steroids provide hope and are thus potential candidates for safer anti-inflammatory for drug development, but may also act as biomarkers of the steroids. 5a-Dihydro- and 5a-tetrahydro-corticosterone can inflammatory status of the liver in metabolic disease. With bind with GRs, but interest in these compounds had been these proposals in mind, careful attention must be paid to the limited, since they only weakly activated metabolic gene possible adverse metabolic effects of 5a-reductase inhibitors, transcription.
    [Show full text]
  • De Novo Androgen Synthesis As a Mechanism Contributing to the Progression of Prostate Cancer to Castration Resistance
    DE NOVO ANDROGEN SYNTHESIS AS A MECHANISM CONTRIBUTING TO THE PROGRESSION OF PROSTATE CANCER TO CASTRATION RESISTANCE by JENNIFER ANN LOCKE B.Sc., The University of British Columbia, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2009 © Jennifer Ann Locke, 2009 Abstract Prostate cancer (CaP) is the leading cause of cancer in men affecting 24,700 Canadians each year and the third leading cause of cancer mortality with 4,300 deaths each year. CaP cells are derived from the prostate secretory epithelium and depend on androgen ligand activation of androgen receptor (AR) for survival, growth and proliferation. Androgen deprivation therapy (ADT) through pharmacological methods has been the leading form of CaP therapy since Huggin‟s discovery that castration induced the regression of CaP tumors in 1941. Unfortunately, the cancer often recurs within 2-4 years in what has classically been considered “androgen-independent” (AI) disease. Growing evidence implicates androgens and AR activation in this disease recurrence despite castration, suggesting that this terminology should be more appropriately called “castration-resistant” prostate cancer (CRPC). Firstly, AR is found amplified, overexpressed or mutated in a majority of recurrent cancers as compared to primary cancers and secondly, intratumoral testosterone levels remain the same pre- and post-ADT. Additionally, the measured intratumoral DHT levels are sufficient to activate AR in recurrent CaP cells despite low serum androgen levels suggesting that intratumoral androgens remain important mediators of AR-mediated CaP progression. Previously, we and others discovered that recurrent tumor cells have elevated levels of enzymes in the pathways necessary for androgen synthesis from cholesterol.
    [Show full text]
  • Structure of Human Steroid 5Α-Reductase 2 with Anti-Androgen
    Structure of human steroid 5α-reductase 2 with anti-androgen drug finasteride Qingpin Xiao1, 5, Lei Wang2, Shreyas Supekar3, Tao Shen4, Heng Liu2, Fei Ye4, Junzhou Huang4, Hao Fan3, Zhiyi Wei1*, Cheng Zhang2* 1Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China 2Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA15261, USA 3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore 4Tencent AI Lab, Shenzhen, Guangdong 518000, China 5Faculty of Health Sciences, University of Macau, Macau SAR 999078, China. *Correspondence: Dr. Zhiyi Wei, [email protected] or Dr. Cheng Zhang, [email protected]. 1 Abstract Human steroid 5α-reductase 2 (SRD5α2) as a critical integral membrane enzyme in steroid metabolism catalyzes testosterone to dihydrotestosterone. Mutations on its gene have been linked to 5α-reductase deficiency and prostate cancer. Finasteride and dutasteride as SRD5α2 inhibitors are widely used anti- androgen drugs for benign prostate hyperplasia, which have recently been indicated in the treatment of COVID-19. The molecular mechanisms underlying enzyme catalysis and inhibition remained elusive for SRD5α2 and other eukaryotic integral membrane steroid reductases due to a lack of structural information. Here, we report a crystal structure of human SRD5α2 at 2.8 Å revealing a unique 7-TM structural topology and an intermediate adduct of finasteride and NADPH as NADP- dihydrofinasteride in a largely enclosed binding cavity inside the membrane. Structural analysis together with computational and mutagenesis studies reveals molecular mechanisms for the 5α- reduction of testosterone and the finasteride inhibition involving residues E57 and Y91.
    [Show full text]
  • 11-Keto-Testosterone and Other Androgens of Adrenal Origin
    Physiol. Res. 69 (Suppl. 2): S187-S192, 2020 https://doi.org/10.33549/physiolres.934516 REVIEW 11-Keto-testosterone and Other Androgens of Adrenal Origin Luboslav STÁRKA, Michaela DUŠKOVÁ, Jana VÍTKŮ 1Institute of Endocrinology, Prague, Czech Republic Received February 20, 2020 Accepted April 14, 2020 Summary half in the adrenals. The androgenic potential of these The adrenal glands produce significant amounts of steroid steroids is low. However, the human adrenal also secretes hormones and their metabolites, with various levels of 11-oxygenated androgens (11-oxy-androgens), including androgenic activities. Until recently, the androgenic potency of 11β-hydroxy-androstenedione. Plasma levels of these adrenal-derived compounds were not well known, but 11β-hydroxy-androstenedione (means ± SD) in healthy some recent studies have shown that the production of 11-oxo- persons in the morning are 8.69±2.88 (men), 7.72±2.85 and 11β-hydroxy-derived testosterone and dihydrotestosterone (women), 8.73±5.13 (boys) and 7.88±5.23 (girls) nmol/l, evidently have high androgenic activity. This fact has clinical respectively. The concentrations of these hormones importance, for instance, in various types of congenital adrenal follow the circadian rhythm pattern of cortisol, increasing hyperplasia with androgenization or polycystic ovarian syndrome, markedly after corticotropin stimulation and suppressed and laboratory determinations of these substances could help to by dexamethasone (Putz et al. 1987). 11β-hydroxy- better evaluate the total androgen pressure in patients with these androstenedione serves as the precursor of several highly disorders. Another area of concern is the treatment of prostate potent androgens, the 11-oxygenated derivatives of cancer with androgen deprivation, which loses effectiveness testosterone and dihydrotestosterone.
    [Show full text]