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Exploring the Steroidogenic Activity of Glutathione Transferases Across Species

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Exploring the Steroidogenic Activity of Glutathione Transferases Across Species Helena Lindström Exploring the steroidogenic activity of glutathione transferases across species Exploring the steroidogenic activity of glutathione transferases across species across transferases glutathione of activity the steroidogenic Exploring Helena Lindström Helena Lindström is an IT-professional gone scientific. After several years in the telecom industry she obtained her M.Sc. in medicinal chemistry and continued to her docotoral studies at Stockholm University. ISBN 978-91-7911-054-3 Department of Biochemistry and Biophysics Doctoral Thesis in Neurochemistry with Molecular Neurobiology at Stockholm University, Sweden 2020 Exploring the steroidogenic activity of glutathione transferases across species Helena Lindström Academic dissertation for the Degree of Doctor of Philosophy in Neurochemistry with Molecular Neurobiology at Stockholm University to be publicly defended on Thursday 7 May 2020 at 10.00 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B. Abstract Glutathione transferases (GSTs) comprise a superfamily of enzymes prominently involved in detoxication. However, some GSTs have developed alternative functions. Thus, a member of the Alpha class GSTs in tissues of Homo sapiens (humans), Sus scrofa (pigs) and ruminants is involved in biosynthesis of steroid hormones, catalyzing a double-bond isomerization reaction as the last step of synthesis of Δ4-pregnene-3,20-dione (progesterone) and the obligatory step in the synthesis of the last precursor of testosterone, Δ4-androstenene-3,17-dione. Steroids regulate several vital aspects of life such as for example glucose homeostasis, inflammation, immunosuppression, blood pressure, reproduction and pregnancy. The human GST A3-3 was the most efficient steroid double-bond isomerase known so far in mammals. Our work extends discoveries of GSTs that act in the steroidogenic pathways in large mammals to Equus ferus caballus (horse). The kinetic profile of EcaGST A3-3 reveals a catalytic efficiency higher than that of the human enzyme making EcaGST A3-3 the most efficient steroid double-bond isomerase known today in mammals. In contrast to the rodents, Equus ferus caballus shares the steroidogenic pathway with Homo sapiens, which makes it a more suitable model for human steroidogenesis than the murine one. Inhibition of EcaGST A3-3 might help treat endocrine disorders. We screened a library of 1040 FDA-approved compounds for novel inhibitors of EcaGST A3-3 and made a further characterization of the most potent inhibitors. To extend the search for steroidogenic GSTs to other mammals, we probed the degree of GST A3-3 amino acid sequence conservation in Homo sapiens, Equus ferus caballus, Canis lupus familiaris (dog), Capra hircus (goat) and Monodelphis domestica (gray short-tailed opossum). We generated expression vectors containing homologous DNA from these species to facilitate further evaluation of the activity of these GSTs in mammals. We continued to expand the research to insects by investigating the steroidogenic activity of GSTE14 in Drosophila melanogaster (fruit fly), where this enzyme has been shown to be implicated in molting. Our work has provided insights into the role of GSTs in steroidogenesis in mammals and insects, further accentuating the functional versatility of GSTs. We have provided an initial step for the development of potential treatments of steroidogenic disorders as well as tools for further investigation of activity of these GSTs in mammals. Keywords: Glutathione transferase, steroidogenesis, GST A3-3, testis, androstenedione, pregnenedione, equine, steroidogenesis inhibition, Drosophila GSTE14. Stockholm 2020 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-179443 ISBN 978-91-7911-054-3 ISBN 978-91-7911-055-0 Department of Biochemistry and Biophysics Stockholm University, 106 91 Stockholm EXPLORING THE STEROIDOGENIC ACTIVITY OF GLUTATHIONE TRANSFERASES ACROSS SPECIES Helena Lindström Exploring the steroidogenic activity of glutathione transferases across species Helena Lindström ©Helena Lindström, Stockholm University 2020 ISBN print 978-91-7911-054-3 ISBN PDF 978-91-7911-055-0 Printed in Sweden by Universitetsservice US-AB, Stockholm 2020 Curiosity killed the cat. (There is no solid evidence for that though.) List of publications i. Lindström, H., Peer, S. M., Ing, N. H. & Mannervik, B. Characterization of equine GST A3-3 as a steroid isomerase. J. Steroid Biochem. Mol. Biol. 178, 117-126 (2018) ii. Lindström, H., Mazari, A. M. A., Musdal, Y. & Mannervik, B. Potent inhibitors of equine steroid isomerase EcaGST A3-3. PLoS ONE, 14(3), e0214160 iii. Peer, S. M., Samollow, P., Lindström, H., Mannervik, B. & Ing, N. H. Conservation of glutathione transferase mRNA and protein sequences similar to human GST Alpha 3 across diverse mammalian species. Manuscript iv. Škerlová, J., Lindström, H., Conis, E., Sjödin, B., Neiers, F., Stenmark, P. & Mannervik, B. Structure and steroid isomerase activity of Drosophila glutathione transferase E14 essential for ecdysteroid biosynthesis. FEBS Lett., 10.1002/1873-3468.13718 Table of contents Abbreviations .................................................................................................. i Introduction .................................................................................................... 1 Detoxication ................................................................................................................... 2 Glutathione transferases ............................................................................................... 3 Glutathione ............................................................................................................... 3 Classification of mammalian GSTs .......................................................................... 4 Nomenclature ........................................................................................................... 4 Species distribution .................................................................................................. 5 Structure ................................................................................................................... 7 Detoxication functions of cytosolic GSTs ................................................................. 8 Endogenous GST substrates ................................................................................... 9 Xenobiotic GST substrates .................................................................................... 11 Biotechnological applications ................................................................................. 12 Alternative functions ............................................................................................... 13 Steroids ....................................................................................................................... 13 Corticosteroids ....................................................................................................... 14 Sex steroids ........................................................................................................... 18 Steroid biosynthesis in mammals ........................................................................... 20 Protective neuro-effects of steroid hormones ........................................................ 22 Role of glutathione transferases in steroid biosynthesis ............................................. 23 The catalytic mechanism ........................................................................................ 23 Steroid biosynthesis in insects .................................................................................... 26 Why this thesis? Hypotheses and aims ....................................................... 27 Methods ....................................................................................................... 29 Heterologous expression ............................................................................................. 29 Reverse transcription PCR (RT-PCR) and nested PCR ........................................ 29 Quantitative RT-PCR (RT-qPCR) .......................................................................... 30 Ligation ................................................................................................................... 30 Electroporation ....................................................................................................... 30 Affinity chromatography ......................................................................................... 31 Kinetic measurements ................................................................................................. 32 Irreproducibility due to loW enzyme concentration ....................................................... 33 Size-exclusion chromatography .................................................................................. 33 X-ray crystallography ................................................................................................... 33 Present investigation .................................................................................... 35 Tissue distribution and kinetic profiles ......................................................................... 35 Tissue distribution .................................................................................................. 35 Kinetic profiles ........................................................................................................ 36 Summary ...............................................................................................................
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