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Glutaminylzyklase (QC)-Inhibierende Verbindungen Aus Mikroalgen – Neue Leitstrukturen Für Den Einsatz in Der Therapie Der Alzheimer Erkrankung

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Glutaminylzyklase (QC)-Inhibierende Verbindungen Aus Mikroalgen – Neue Leitstrukturen Für Den Einsatz in Der Therapie Der Alzheimer Erkrankung Glutaminylzyklase (QC)-inhibierende Verbindungen aus Mikroalgen – neue Leitstrukturen für den Einsatz in der Therapie der Alzheimer Erkrankung Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Naturwissenschaftlichen Fakultät I – Biowissenschaften – der Martin-Luther-Universität Halle-Wittenberg, vorgelegt von Frau Dipl. Ing. (FH) Stephanie Hielscher-Michael geb. am 21.06.1978 in Wippra Die vorliegende Arbeit entstand im Zeitraum von Januar 2009 bis Dezember 2013 in der Ar- beitsgruppe Biochemie/ Algenbiotechnologie der Hochschule Anhalt in Köthen (Frau Prof. Dr. Carola Griehl), im Leibniz-Instituts für Pflanzenbiochemie in der Abteilung Natur- und Wirkstoffchemie (Herr Prof. Dr. Ludger Wessjohann) und der Probiodrug AG (Herr Prof. Hans-Ulrich Demuth jetzt Fraunhofer-Institut für Zelltherapie und Immunologie IZI, Außen- stelle Halle für Molekulare Wirkstoffbiochemie und Therapieentwicklung) im Rahmen eines kooperativen Promotionsverfahrens mit der Martin-Luther-Universität Halle Wittenberg (Herrn Prof. Dr. Markus Pietzsch, Arbeitsgruppe Aufarbeitung biotechnischer Produkte, Institut für Pharmazie der Naturwissenschaftlichen Fakultät I). Die Algenkultivierungen wurden im Algenbiotechnikum der Hochschule Anhalt in Köthen un- ter der Betreuung von Frau Prof. Dr. Carola Griehl durchgeführt. Die Arbeiten zur Identifizie- rung, Charakterisierung sowie Isolierung der QC-inhibierenden Verbindungen erfolgten am Leibniz-Institut für Pflanzenbiochemie in der Abteilung Natur- und Wirkstoffchemie unter An- leitung von Herrn Prof. Dr. Ludger Wessjohann. Die Testungen im QC-Assay wurden in der Probiodrug AG unter Betreuung von Herrn Prof. Hans-Ulrich Demuth jetzt Fraunhofer-Institut für Zelltherapie und Immunologie IZI durchgeführt. Gutachter: 1. Prof. Dr. Markus Pietzsch Martin-Luther-Universität Halle-Wittenberg; Naturwissenschaftliche Fakultät I- Biowissenschaften, Institut Pharmazie, Halle/S. 2. Prof. Dr. Ludger Wessjohann Leibniz-Institut für Pflanzenbiochemie; Abteilung Natur- und Wirkstoffchemie, Halle/S. 3. Prof. Dr. Carola Griehl Hochschule Anhalt; Fachbereich Angewandte Biowissenschaften und Prozesstechnik, Köthen Tag der öffentlichen Verteidigung: 24.01.2017 in Halle Gewidmet meiner Familie Inhaltsverzeichnis Inhaltsverzeichnis ............................................................................................................................. I Abkürzungen ............................................................................................................................ IV 1. Zusammenfassung ................................................................................................................... 1 2. Summary ............................................................................................................................. 3 3. Einleitung und Zielstellung ....................................................................................................... 5 4. Stand des Wissens .................................................................................................................. 7 4.1. Algen als Quelle bioaktiver Verbindungen ...........................................................................7 4.2. Alzheimer Erkrankung (AD) .............................................................................................. 11 4.2.1. Epidemiologie und Risikofaktoren ............................................................................... 11 4.2.2. Symptomatik und Verlauf ............................................................................................. 12 4.2.3. Neuropathologische Charakteristika ............................................................................ 12 4.2.4. Pathogenese ............................................................................................................ 14 4.2.4.1. APP-Prozessierung und Aβ-Peptide............................................................................ 15 4.2.4.2. Amyloid Kaskaden Hypothese ..................................................................................... 18 4.2.5. Derzeitige Therapieoptionen ........................................................................................ 19 4.2.6. Perspektivische Therapieansätze (AD Targets) .......................................................... 21 4.2.6.1. Therapieansatz: Hemmung der QC ............................................................................. 30 5. Ergebnisse & Diskussion ....................................................................................................... 35 5.1. Kultivierung der Mikroalgen .............................................................................................. 35 5.2. Extraktion und Extraktaufarbeitung ................................................................................... 37 5.3. Screening der Algenextrakte auf QC-inhibierende Eigenschaften ................................... 39 5.3.1. Parameterbestimmung für den QC-Assay ................................................................... 40 5.3.1.1. Michaelis-Menten Konstante Km .................................................................................. 40 5.3.1.2. Einfluss der Lösungsmittel ........................................................................................... 40 5.3.2. QC-inhibierende Wirkungen der Algenextrakte ........................................................... 41 5.3.2.1. Untersuchung der konzentrationsabhängigen QC-Inhibierung ................................... 42 5.4. Identifizierung QC-inhibierender Metaboliten ................................................................... 42 5.4.1. Identifizierung QC-inhibierender Metaboliten mittels bioaktivitäts-geleiteter Isolierung ............................................................................................................ 43 5.4.2. Identifizierung QC-inhibierender Metaboliten mittels AcorA ........................................ 49 5.4.2.1. Massenspektrometrische Untersuchungen ................................................................. 50 5.4.2.2. Korrelationsanalyse (AcorA) ........................................................................................ 52 5.4.2.3. Strukturelle Charakterisierung der identifizierten QC-aktivitätsrelevanten Metaboliten ............................................................................................................ 64 5.4.3. Untersuchungen der identifizierten QC-aktivitätsrelevanten Metaboliten mittels Molecular Modeling ...................................................................................................... 75 5.4.4. Aktivitätsnachweis der identifizierten QC-aktivitätsrelevanten Metaboliten ................. 78 I 5.4.5. Isolierung der QC-aktiven Metaboliten (Sulfolipide) .................................................... 79 5.5. Charakterisierung weiterer Algenmetabolite ..................................................................... 83 5.6. Diskussion der erzielten Ergebnisse und durchgeführten Arbeiten .................................. 93 5.6.1. Sulfolipide – neue QC-inhibierende Verbindungen aus Mikroalgen ............................ 93 5.6.2. Identifizierung und Charakterisierung der QC inhibierenden Sulfolipide ..................... 96 6. Material und Methoden ........................................................................................................ 102 6.1. Verwendete Geräte und Chemikalien ............................................................................. 102 6.2. Kultivierung der Mikroalgen ............................................................................................ 104 6.2.1. Verwendete Mikroalgenspezies ................................................................................. 104 6.2.2. Verwendete Medien und Kultivierungsbedingungen ................................................. 104 6.2.3. Kultivierung im Labormaßstab (Vorkultur/Inokulum) ................................................. 105 6.2.4. Kultivierung im Technikumsmaßstab ......................................................................... 105 6.2.5. Prozessbegleitende Analytik ...................................................................................... 106 6.2.5.1. Bestimmung der Biotrockenmassekonzentration ...................................................... 106 6.2.5.2. Bestimmung Zellzahl .................................................................................................. 106 6.2.5.3. Bestimmung der maximalen spezifischen Wachstumsrate ....................................... 106 6.2.6. Ernte der Biomasse ................................................................................................... 106 6.3. Zellaufschluss und Extraktion ......................................................................................... 107 6.3.1. Dreistufige Extraktion ................................................................................................. 107 6.3.2. Einstufige Extraktion .................................................................................................. 107 6.4. Extraktaufarbeitung / Probenvorbereitung ...................................................................... 108 6.4.1. Chlorophyll-Entfernung .............................................................................................. 108 6.4.1.1. Chlorophyllfällung modifiziert nach Greilinger und Gross .......................................... 108 6.4.1.2. Chlorophyll-Eliminierung mittels SA-Kartuschen ......................................................
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