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Non-Enzymatic Regeneration of Ergothioneine After Reaction with Singlet Oxygen

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Non-Enzymatic Regeneration of Ergothioneine After Reaction with Singlet Oxygen Non-enzymatic regeneration of ergothioneine after reaction with singlet oxygen Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Mhmd Oumari aus Hasaka / Syrien Düsseldorf, Juli 2019 aus dem Institut für Pharmakologie der Universität zu Köln Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Berichterstatter: 1. Prof. Dr. Peter Proksch 2. Prof. Dr. Dirk Gründemann Tag der mündlichen Prüfung: 18.09.2019 = Eidesstattliche Versicherung Ich versichere an Eides Statt, dass die Dissertation von mir selbstständig und ohne unzulässige fremde Hilfe unter Beachtung der “Grundsätze zur Sicherung guter wissenschaftlicher Praxis an der Heinrich-Heine-Universität Düsseldorf” erstellt worden ist. Gedankengut oder Daten, die aus fremden Quellen entliehen wurden, sind kenntlich gemacht. Diese Dissertation ist von mir noch an keiner anderen Stelle vorgelegt worden. Ich habe vormals noch keinen Promotionsversuch unternommen. Düsseldorf, Juli 2019 ………………………… (Mhmd Oumari) > Acknowledgments First of all, I would like to profoundly thank Professor Dr. Dirk Gründemann for awarding me the project, the friendly support and the opportunity to do my PhD in his work group. It has been an honor to be his student. I am very grateful to Professor Dr. Peter Proksch for his support and allowing me to do my PhD thesis at the University of Düsseldorf. I would like to thank our co-operation partners, Professor Dr. Bernd Goldfuss for his support through Density Functional Theory (DFT) computations, and Professor Dr. Hans-Günther Schmalz for the synthesis of endoperoxide (DHPNO2). I would also like to thank the members of the work group of Professor Dr. Dirk Gründemann and my colleagues Kathi, Samira, Simone, Julia, Julian, Chih-hsuan and Lea, as well as previous colleagues, Peter and Christopher for the great working atmosphere and their support. I would like to thank my family, parents, siblings and friends for their support and motivation during my PhD and in all aspects of life. ? Publications 1) Oumari, M., B. Goldfuss, C. Stoffels, H.G. Schmalz and D. Grundemann, Regeneration of ergothioneine after reaction with singlet oxygen. Free Radic Biol Med, 2019. 134: p. 498-504. 2) Stoffels, C., M. Oumari, A. Perrou, A. Termath, W. Schlundt, H.G. Schmalz, M. Schafer, V. Wewer, S. Metzger, E. Schomig and D. Grundemann, Ergothioneine stands out from hercynine in the reaction with singlet oxygen: Resistance to glutathione and TRIS in the generation of specific products indicates high reactivity. Free Radic Biol Med, 2017. 113: p. 385-394. @ Abstract Ergothioneine (ET) is a histidine betaine derivative with a sulfur atom attached to the 1 position two of the imidazole ring. As established, ET eradicates singlet oxygen ( O2) and has been considered an antioxidant. Various functions of ET regarding reactive oxygen species (ROS) have been proposed and much progress concerning ET has been attained. However, no mechanism for the regeneration of ET after a reaction with ROS has been determined. In fact, if ET is an important antioxidant, like ascorbate, glutathione (GSH), ubiquinol and vitamin E, and if the benefit of ET in living organisms is continual and does not lose its capacity to eradicate oxidants after a single chemical reaction, then the ET should be regenerated from its oxidized product so as to be an efficient antioxidant. In this work, a non-enzymatic mechanism 1 for the regeneration of ET after reaction with O2 was discovered. For this 1 mechanism, four molecules of GSH are needed to detoxify O2 into water and 1 oxidized GSH (GSSG) as a by-product. Clean O2 was generated by thermolysis at 37 °C of the endoperoxide DHPNO2. Addition of 1 mM ET to 10 mM DHPNO2 and 10 mM GSH increased the production of GSSG by factor of 26 (in water) and 28 (D2O), respectively, measured by means of LC-MS/MS. The ring of ET was responsible for the whole reaction cycle and the zwitterionic amino acid backbone was not involved, since only the ring of ET, and 4-methyl ET ring significantly generated GSSG, with equally high intensity as ET. According to the results from the production of GSSG in 1 the present work, the data suggest that ET reacts with O2 150-fold more efficiently 1 than GSH, and ET reacts at least 4-fold faster than ascorbic acid towards O2. The necessary thiol foundation (GSH) exists naturally in all mammalian and vertebrate cells as well as in all species that produce ET, such as cyanobacteria, mycobacteria, and fungi with relatively high intracellular concentrations (5 - 10 mM). The byproduct GSSG, regenerates to GSH in living organisms by glutathione reductase, utilizing a NADPH dependent-enzyme. Based on that, ET must now be viewed as closely linked with the redox couple GSH/GSSG. These findings prove the importance of ET over other reactive compounds, that are non-recoverable, for the detoxification of noxious 1 O2. 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