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SDR and AKR Enzymes As a Target of Rational Inhibitor Development and Research on Functions of New SDR Members

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SDR and AKR Enzymes As a Target of Rational Inhibitor Development and Research on Functions of New SDR Members TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Experimentelle Genetik SDR and AKR enzymes as a target of rational inhibitor development and research on functions of new SDR members Dorota Patrycja Kowalik Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernärung Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigte Dissertation. Vorsitzender: Univ.-Prof. Dr. Martin Hrabe de Angelis Prüfer der Dissertation: 1. apl. Prof.Dr. Jerzy Adamski 2. Univ.-Prof. Dr. Johannes Buchner Die Dissertation wurde am 09.05.2016 bei der Technischen Universität München eingereicht und durch die Fakultät für Wissenschaftszentrum Weihenstephan für Ernärung Landnutzung und Umwelt der Technischen Universität München am 25.11.2016 angenommen. Zusammenfassung Hydroxysteroiddehydrogenasen (HSDs) spielen eine bedeutende Rolle in Regulierung der Biosynthese von Steroidhormonen und gehören zur zwei großen Familien der Enzymen: short chain dehydogenases (SDR) und der aldo-keto reductases (AKR). Die Fehlregulierung einiger HSD-Aktivitäten führt zu verschiedenen schweren Störungen wie Alzheimer Syndrom oder hormonabhängigem Krebs. Deshalb stellen die HSDs schon seit vielen Jahren interessante Ziele für die der pharmazeutische Industrie für die Entwicklung neuer spezifischer Inhibitoren dar. Zwei der 17β-Hydroxysteroid dehydrogenasen, die 17β-Hydroxysteroiddehydrogenase Typ 3 (zur Familie der short chain dehydogenases (SDRs) gehörend) und die 17β-Hydroxysteroid Dehydrogenase Typ 5 (eine Aldo-Keto Reduktase (AKR)), katalysieren die Testosteron Biosynthese und ihre Überaktivität wird assoziiert mit einigen Krankheiten wie Prostatakrebs. Die Fortschritte in der Bioinformatik und Computer-basierten Methoden für Molekulare Modellierung ermöglichen Hochdurchsatz-Screening Methoden und erleichtern erheblich die systematische Entwicklung neuer enzym-spezifischer Liganden mit den gewünschten Eigenschaften, die später als Medikamente dienen könnten. Kooperierende Forscher der pharmazeutische Firma BioNetWorks und eines Forschungsteams der Universität Innsbruck entwickelten zwei Ligand- und Struktur -basiert Pharmakophormodelle und wendeten diese an, um neue mögliche Inhibitoren gegen die Aktivitäten der 17β-Hydroxysteroiddehydrogenasen Typ 3 und 5 zu identifizieren. In der vorliegenden Arbeit wurden dann 35 verschiedene, durch das in silico Screening ausgewählte Chemikalien zur biologischen Prüfung und Bewertung untersucht. Aus dieser Gruppe wurden einige zukunftsträchtige Substanzen als 17β-HSD3 oder 5 Inhibitoren für weitere mehr detailliert biologische Prüfungen identifiziert. Einer der Inhibitor-Kandidaten gegen die reduktive Aktivität der 17β-HSD5 zeigte sogar eine Hemmwirkung im nanomolaren Bereich und wurde daher detailierter untersucht. Ein Ki von 180 nM und IC50 Werte in Bereich zwischen 140nM und 290nM, abhängig von der Sorte der enzymatischen Assay, wurden ermittelt. Darüber hinaus wurden 3 in der Forschungsliteratur kaum annotierte humane SDR-Enzyme, die einige Ähnlichkeiten zu gut bekannten Hydroxysteroiddehydrogenasen zeigen, in dieser Doktorarbeit detaillierter charakterisiert: Hydroxysteroiddehydrogenase Typ 8 (HSD17B8), SDR-O (SDR-Orphan) und die Hydroxysteroiddehydrogenase like 2 (HSDL2). Um die Bedeutung für die mögliche Funktionen der Enzyme im Menschen zu erfassen wurden Experimente wie z.B. subzelluläre Lokalisierung durchgeführt, sowie enzymatische Tests zur Überprüfung der Aktivität mit Steroiden und Retinoiden. Während das bevorzugte Vorkommen für zwei der Enzyme einwandfrei festgestellt werden konnte, HSD17B8 findet man in Mitochondrien und HSDL2 in den Peroxisomen oder Mitochondrien, bleibt es für SDR-O ungeklärt. Von den drei Enzymen zeigte nur HSD17B8 eine enzymatische Aktivität mit einem Steroidsubstrat, dem Estradiol, und nur SDR-O eine schwache Aktivität mit einem Retinoid, dem Retinal in Gegenwart von NADH. i Abstract Hydroxysteroid dehydrogenases (HSDs) play a key role in the regulation of the steroid hormone metabolism and belong to two protein superfamilies the short-chain dehydrogensases/reductses (SDR) and the aldo-keto reductases (AKR). Up-regulation of their enzymatic activity can be involved in pathogenesis of many serious disorders in humans like Alzheimer’s disease or hormone-dependent cancers. Thus, since many years HSDs constitute interesting targets for the development of specific inhibitors which could be applied as potent therapeutic drugs. Two of the 17β-hydroxysteroid dehydrogenases, the 17β-hydroxysteroid dehydrogenase type 3 belonging to the SDRs and 17β-hydroxysteroid dehydrogenase type 5 (belonging to the aldoketo reductases (AKRs), catalyze reactions of the testosterone biosynthesis and an enhanced activity of the enzymes is linked to several androgen-related illnesses such as for example prostate cancer. Nowadays due to advances in bioinformatics as well computational methods of molecular modelling high throughput rational approaches for designing new enzyme-specific inhibitors are available. Co-operating researchers of the company BioNetWorks and the University Innsbruck developed two ligand-and structure-based pharmacophore models and applied those to identify potential inhibitors for 17βHSD3 and 5. By this in silico screen, 35 chemically diverse compounds we found as potent candidate inhibitors. In this PhD work here the 35 candidate compounds were subjected to biological evaluation. This allowed to discover some promising compounds, which could be lead structures for further researching or pharmacological tools in future projects. One of the compounds against the reductive activity of 17βHSD5 even displayed an inhibitory activity in the nanomolar range and therefore was characterized in more detail. For this compound a Ki of 180 nM and IC50 values ranging between 140nM and 290nM, were found, depending on the kind of enzymatic assay applied. Moreover, not all recently identified SDRs have been analyzed in detail yet. Three barely annotated human SDR candidates, which reveal some similarities to known hydroxysteroid dehydrogneses, were chosen in this PhD work for further characterization: hydroxysteroid dehydrogenase type 8 HSD17B8, an orphan SDR (SDR-O) and hydroxysteroid dehydrogenase like 2 (HSDL2). In search for their potent functions in human results for e.g., subcellular localization, bioinformatics studies based on sequence analysis of primary amino acid structure as well enzymatic tests checking the activities towards steroid and retinoid substrates are here presented. Two of the enzyme could be assigned to cellular compartments, HSD17B8 to mitochondria, HSDL2 to peroxisomes or mitochondria, while the preferred location of SDR-O remains unclear. Of the three enzymes only HSD17B8 showed an enzymatic activity with a steroid substrate, in that case estradiol, and only SDR-O was able to metabolize a retinoid compound, i.e., weak activity towards retinaldehyde in the presence of NADH as cofactor was observed with the human SDR-O gene. ii List of Abbreviations AKR aldo-keto reductase APS ammoniumperoxodisulfat cDNA complementary deoxyribonucleic acid DAPI 4′,6-Diamidino-2-phenylindole,dihydrochlorid DMSO dimethylsulfoxid DNA deoxyribonucleic acid dNTP desoxyribonucleoside triphosphate ds double strand EDTA ethylendiamintetraacetat ER endoplasmatic retikulum EST expressed sequence tag et al. et alteri FBS fetal bovine serum GFP green fluorescent protein GST gluthation-S-transferase HMGU Helmholtz Zentrum München – Deutsches Forschungszentrum für Gesundheit und Umwelt HPLC High Pressure Liquid Chromatography HRP Horse raddish peroxidase HSD Hydroxysteroid dehydrogenase HSD17BX 17β-Hydroxysteroid dehydrogenase Type X IPTG isopropyl-β-D-thiogalactoside IEG Institute of Experimental Genetics kb kilobase paar kDa kilodalton λ lambda, wavelength NAD+ nicotinamide adenine dinucleotide, oxidized NADH nicotinamide adenine dinucleotide, reduced NADP nicotinamide adenine dinucleotide phosphate, oxidized NADPH nicotinamide adenine dinucleotide phosphate, reduced OD optical density ORF open reading frame PBS phosphate buffered saline PCR polymerase chain reaction PDB protein data bank RDH retinol dehydrogenase RNA ribonucleic acid rpm rotation per minute SDR short-chain dehydrogenase/reductase SDS-PAGE sodium dodecyl sulfate - polyacrylamide gel electrophoresis TEMED tetramethylethylendiamine iii 1 INTRODUCTION ................................................................................................................... 1 1.1 Introduction into SDR protein superfamily .............................................................................................. 1 1.1.1 Structural aspects of SDRs ............................................................................................................................................. 1 1.1.2 Classification criteria of SDR families ....................................................................................................................... 3 1.1.3 Enzymatic activities and substrate specificity ...................................................................................................... 4 1.1.4 Mechanism of catalyzed reaction ............................................................................................................................... 6 1.2 Short introduction into AKR enzyme superfamily ................................................................................. 8 1.3 Control of biological processes ...................................................................................................................
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