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Molecular Regulation of Adrenal Androgen Biosynthesis Molecular Regulation of Adrenal Androgen Biosynthesis by Jan Idkowiak A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Clinical and Experimental Medicine College of Medical and Dental Sciences University of Birmingham August 2014 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. “More valuable than treasures in a storehouse are the treasures of the body, and the treasures of the heart are the most valuable of all. From the time you read this letter on, strive to accumulate the treasures of the heart!” Nichiren Daishonin (1222-1282) II Abstract ___________________________________________________________________ Abstract The biosynthesis of adrenal androgens is catalysed by steroid-modifying enzymes. Over the past decade, co-factors were explored to regulate these enzymes: P450 oxidoreductase (POR) delivers electrons to the key androgen-producing cytochrome P450 enzyme CYP17A1. In addition, sulfation of the principal androgen precursor dehydroepiandrosterone (DHEA) catalysed by the enzyme SULT2A1, supported by its co- factor 3’-phosphoadenosine-5’-phosphosulfate (PAPS) synthase 2 (PAPSS2), has been found more recently as a gatekeeper of androgen activation. Here, we have further characterised children with defects of enzymes of the androgen pathway, namely CYP17A1 and POR. We report the first human missense mutation of cytochrome b5, which supports electron transfer from POR to CYP17A1. In addition, we have explored the molecular regulation of DHEA sulfation by in vitro and in vivo studies. The results from our studies provide important information on the clinical course, the diagnostic steroid fingerprint and underlying molecular mechanisms of conditions affecting androgen generation. The in vitro studies on DHEA sulfation confirm that the PAPSS2 isoform crucially regulates SULT2A1. Our in vivo study in children with deficiencies of the steroid sulfatase (STS) enzyme, the counterpart of SULT2A1, suggests that STS does not play a major role in DHEA metabolism but is more active before puberty. III Acknowledgements ___________________________________________________________________ Acknowledgements I would like to express my gratitude to my supervisor, Prof Wiebke Arlt, for all her support, personal encouragement and foremost for her never ceasing confidence in this work. I am also grateful to my co-supervisor Prof Tim Barrett for his support. I feel very fortunate to be part of the entire Arlt group and of the Centre of Endocrinology, Diabetes and Metabolism (CEDAM), where I met many wonderful people, great scientists and friends. I wish to thank them all, but I would like to specifically thank for their great support, friendship and laughter: Dr Vivek Dhir, Dr Nils Krone, Dr Silvia Parajes, Dr Nicole Reisch, Dr Jon Mueller, Mr Ian Rose, Dr Iwona Bujalska, Dr Mark Sherlock, Dr Laura Gathercole and Dr Fabian Hammer. A special thanks to Hannah Ivison for proofreading this thesis and (hopefully) correcting my Germanisms. Thanks to mum and dad, who are supporting me throughout and are tolerant enough for me going away from Germany to seek my life and work mission in the UK, where I met my wonderful wife Vicki and her children Jamila and Jake. I am grateful to you all!! I wish to dedicate this thesis to my mentor in life, Dr Daisaku Ikeda. IV Table of Contents ___________________________________________________________________ Table of contents 1.! Chapter 1: General Introduction ........................................................................ 1! 1.1.! The adrenal cortex and steroid biosynthesis ............................................................ 2! 1.1.1.!Anatomy, function and regulation of the adrenal gland ............................................... 2! 1.1.2.!Principles of steroid hormone biosynthesis and action ................................................ 4! 1.1.3.!Co-factor regulation of steroidogenesis ....................................................................... 8! 1.1.3.1.! Adrenodoxin (Adx) and Adrenodoxin reductase (AdR) ................................................... 9! 1.1.3.2.! P450 oxidoreductase (POR) ........................................................................................... 9! 1.1.3.3.! Cytochrome b5 (CYB5A) .............................................................................................. 11! 1.1.4.!The first step in human steroidogenesis .................................................................... 12! 1.1.5.!Principles of steroid hormone action ......................................................................... 15! 1.1.6.!Mineralocorticoids (MC) ............................................................................................. 17! 1.1.6.1.! MC biosynthesis ........................................................................................................... 17! 1.1.6.2.! MC regulation ............................................................................................................... 19! 1.1.6.3.! MC action ...................................................................................................................... 19! 1.1.7.!Glucocorticoids (GCs) ............................................................................................... 20! 1.1.7.1.! GC biosynthesis ............................................................................................................ 20! 1.1.7.2.! GC regulation and metabolism ..................................................................................... 21! 1.1.7.3.! GC action ...................................................................................................................... 24! 1.1.8.!Androgen precursors ................................................................................................. 26! 1.1.8.1.! Biosynthesis of DHEA ................................................................................................... 26! 1.1.8.2.! Regulation of adrenal androgen secretion .................................................................... 28! 1.1.8.3.! Adrenal androgens and androgen receptor activation .................................................. 29! 1.1.8.4.! Conversion of DHEA to active androgens .................................................................... 30! 1.1.9.!DHEA sulfation pathways and interconversion of DHEA and DHEAS ...................... 33! 1.1.9.1.! DHEA sulfotransferase (SULT2A1) and 3’-phosphoadenosine-5’-phosphosulfate (PAPS) synthases (PAPSS) ............................................................................................... 33! 1.1.9.2.! Steroid sulfatase (STS) and sulfatase-modifing factors (SUMFs) ................................ 37 V Table of Contents ___________________________________________________________________ 1.2.! Adrenal androgens during human pre- and postnatal development .................... 39! 1.2.1.!The adrenal gland during foetal development ........................................................... 39! 1.2.2.!Sex determination and differentiation ........................................................................ 40! 1.2.3.!Adrenarche ................................................................................................................ 43! 1.3.! Androgens and human disease ................................................................................ 46! 1.3.1.!Monogenic causes of impaired androgen synthesis and metabolism ....................... 46! 1.3.1.1.! CYP17A1 17α-hydroxylase deficiency and isolated 17,20 lyase deficiency ................. 48! 1.3.1.2.! P450 oxidoreductase deficiency (apparent combined 21-hydroxylase and 17- hydroxylase deficiencies) .................................................................................................... 50! 1.3.1.3.! CRD and ACRD (HSD11B1 and H6PDH deficiencies) ................................................ 55! 1.3.1.4.! PAPSS2 and apparent DHEA sulfotransferase deficiency ........................................... 57! 1.3.2.!Premature adrenarche ............................................................................................... 58! 1.3.2.1.! Metabolic risk in premature adrenarche ....................................................................... 61! 1.4.! Aims and hypotheses ................................................................................................ 62! 2.! Chapter 2: General Methods ............................................................................ 64! 2.1.! Cell culture techniques .............................................................................................. 64! 2.1.1.!Human embryonic kidney (HEK) 293 cells ................................................................ 64! 2.1.2.!COS7 cells ................................................................................................................. 64! 2.1.3.!NCI-H295R cells .......................................................................................................
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