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Amino Acid Analysis in Biological Fluids by GC-MS

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Amino Acid Analysis in Biological Fluids by GC-MS View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Regensburg Publication Server Amino acid analysis in biological fluids by GC-MS Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Hannelore Kaspar aus Fürstenfeldbruck Juni 2009 Diese Doktorarbeit entstand in der Zeit von Oktober 2005 bis Juni 2009 am Institut für Funktionelle Genomik der Universität Regensburg. Die Arbeit wurde angeleitet von Prof. Dr. Peter J. Oefner. Promotionsgesuch eingereicht im Juni 2009 Kolloquiumstermin: 17.07.2009 Prüfungsausschuß: Vorsitzender: Prof. Dr. Manfred Scheer Erstgutachter: Prof. Dr. Frank-Michael Matysik Zweitgutachter: Prof. Dr. Peter J. Oefner Drittprüfer: Prof. Dr. Jörg Heilmann Für meine Eltern Danksagung Diese Doktorarbeit ist ein großer Meilensteil in meinem bisherigen Leben, den ich durch großartige Unterstützung von vielen lieben Leuten meistern konnte. Den allerwichtigsten Menschen möchte ich hier danken. Als erstes bedanke ich mich bei Prof. PJ. Oefner dafür in seinem Institut promovieren zu dürfen sowie für seinen unermüdlichen Einsatz seinen Mitarbeitern stets die besten Möglichkeiten in Sachen Forschung zu bieten und Kooperationen aufzubauen und zu fördern. Ein besonderes Dankeschön geht auch an Prof. Matysik für die freundliche Übernahme des Erstgutachtens. Bei Prof. Heilmann bedanke ich mich für die Bereitschaft an meiner Prüfung teilzunehmen sowie Prof. Scheer für die Übernahme des Prüfungsvorsitzes. Den allergrößten Dank möchte ich meiner Betreuerin und Mentorin Dr. Katja Dettmer aussprechen. Nicht nur für ihre hervorragende fachliche Betreuung währen meiner Doktorarbeit sondern auch für die vielen freundlichen und aufbauenden Worte, die Weitergabe ihres Wissens und vor allem dafür, dass Sie mir das Gefühl gab als Mensch und Wissenschaftler wichtig und wertvoll zu sein. Vielen Dank an unsere Kooperationspartner Queenie Chan für die statistischen Auswertungen des Methodenvergleichs und allen Mitgliedern der INTERMAP-Studie für die Zusammenarbeit und die Bereitstellung von Messdaten und Probenmaterial, besonders Prof. Elliott, Prof Stammler und Prof Daviglus. Vielen Dank an S. Daniel und S.Nimkar für die Durchführung der iTRAQ® Messungen und die fruchtbaren Diskussionen. Ich bedanke mich bei BayGene für die Finanzierung, bei der Fachgruppe Analytische Chemie (GDCh) und dem Arbeitskreis Separation Science für Stipendien sowie der Arbeitsgruppe Karst für die Organisation des Doktorandenseminars und der ISC. Ich möchte mich auch bei allen Metabolomicsianern für die angenehme und motivierende Zusammenarbeit bedanken: Axel Stevens, vor allem für die Hilfe am Q-Trap, Martin Almstetter für die Aufnahme in die Jean Pierre-Runde, Magda Waldhier dafür dass Sie mit mir die Vorliebe für Aminosäuren teilt und ihre Hilfbereitschaft, Nadine Nürnberger für den Support im Labor und ihre Begeisterung an der Wissenschaft (mit niemand anderem habe ich so gerne Quelle geputzt), Stephan Fargerer für die Vorarbeiten an der LC-MS/MS und seine fröhliche Art, Michael Gruber für die Hilfe jeglicher Art und seine ansteckende gute Laune. Besonders möchte ich auch bei meinen Jungs im Büro bedanken, vor allem Christian Kohler und Claudio Lottaz, die mich nach missglückten Versuchen aufgemuntert- und mir die Freitagnachmittage versüßt haben (In Gedanken werde ich noch lange dem „Streberzimmer“ angehören). Wolfram Gronwald und Claudio danke ich aber auch für die aufbauenden Worte, ihr offenes Ohr, ihren Glauben an mich und mein Können und dafür, dass Sie immer ein Lächeln übrig hatten - für mich seit Ihr das perfekte Vorbild eines Wissenschaftlers. Rainer Spang danke ich für das Asyl in seinen Büroräumen und der gesamten Arbeitsgruppe Spang danke ich vor allem für den Zusammenhalt in den letzten paar Monaten. Ich werde immer zu Euch und Eurem Können aufsehen. Allen gegenwärtigen und ehemaligen Arbeitskreismitgliedern der AG Oefner möchte ich für die Hilfsbereitschaft und Zusammenarbeit danken, insbesondere Sabine Botzler und Corinna Feuchtinger für die Organisation von Festen, Ausflügen und Sabine noch für alle möglichen Formularitäten, Sophie Hinreiner für die netten letzen Monate zusammen im Büro, Mareike Muth für die Bereitstellung von Probenmaterial, Yvonne und Jörg Reinders für Tipps und die viele Schokolade, Marian Thieme für die Beantwortung zahlreicher Computerfragen, Astrid Bruckmann fürs gemeinsame Lachen, Georg Hölzl für die gemeinsamen ersten Gehversuche im GC-Bereich und Steffi Stöckl für die Arbeit als F-Praktikantin. Nicht zu vergessen vielen lieben Dank an Birgit Timischl und Anne Hartmann für die vielen Erklärungen und das gemeinsame Erörtern von Problemen und vor allem für die Freundschaft von Anfang an (auch für die ein oder andere Adventure Tour). Ich hatte immer das Glück wunderbare Freunde um mich zu haben, die mich in Tiefen aufgefangen und mit mir gemeinsam die Höhen genossen haben. Deswegen sage ich Danke an meine Kletterfreunde Josef, Wastl und vor allem dem Energiebüdel Bianka und an meine langjährigen beste Freunde Jassi, Dea und Angelika. Liebe ist das größte Geschenk und deswegen fühle ich mich glücklich meine Liebe gefunden zu haben, dafür danke ich meinen wunderbaren Freund Laiß, der mir zuhört, mich versteht und mir zeigt, dass ich etwas Besonderes bin. Von ganzem Herzen bedanke ich mich bei meiner Familie, meiner Mum und meinem Dad, die mich bedingungslos unterstützen, mich bei allen Höhen und Tiefen auffangen und mir immer wieder Kraft geben alle Anstrengungen und Schwierigkeiten erfolgreich bewältigen zu können. Bedanken möchte ich mich auch bei meinem Bruder Ludwig der mich durch seine Art immer wieder motivierte und für mich stets als Vorbild fungiert hat. 3 1 Table of Contents 1 TABLE OF CONTENTS............................................................................................................ I 2 ABBREVIATIONS AND ACRONYMS..................................................................................V 3 MOTIVATION............................................................................................................................1 4 BACKGROUND .........................................................................................................................4 4.1 METABOLOMICS .......................................................................................................................4 4.2 AMINO ACIDS.............................................................................................................................5 4.3 GAS CHROMATOGRAPHY (GC) ................................................................................................8 4.3.1 PRINCIPLE OF GC ....................................................................................................................8 4.3.2 GAS CHROMATOGRAPHIC COLUMNS AND STATIONARY PHASE ............................................10 4.4 AMINO ACID ANALYSIS FOR METABOLOMICS.......................................................................13 4.4.1 SAMPLE PREPARATION ..........................................................................................................14 4.4.2 LIQUID CHROMATOGRAPHIC METHODS COUPLED WITH OPTICAL DETECTION......................16 4.4.3 ION PAIR REVERSED-PHASE LIQUID CHROMATOGRAPHY – TANDEM MASS SPECTROMETRY (IP-LC-MS/MS)....................................................................................................................20 4.4.4 HILIC (HYDROPHILIC INTERACTION LIQUID CHROMATOGRAPHY).....................................21 4.4.5 CAPILLARY ELECTROPHORESIS MASS SPECTROMETRY (CE-MS).........................................22 4.4.6 GAS CHROMATOGRAPHY FOR AMINO ACID ANALYSIS..........................................................22 4.4.7 ITRAQ®-LC-MS/MS ............................................................................................................24 4.4.8 DIRECT INFUSION TANDEM MASS SPECTROMETRY ...............................................................26 4.4.9 NUCLEAR MAGNETIC RESONANCE (NMR)............................................................................27 4.4.10 COMPARISON OF METHODS FOR AMINO ACID ANALYSIS ....................................................29 5 HIGH-THROUGHPUT ANALYSIS OF FREE AMINO ACIDS IN BIOLOGICAL FLUIDS BY GC-MS .................................................................................................................34 5.1 INTRODUCTION .......................................................................................................................34 5.2 MATERIALS AND METHODS....................................................................................................34 I 5.2.1 CHEMICALS ...........................................................................................................................34 5.2.2 BIOLOGICAL SAMPLES...........................................................................................................35 5.2.3 INSTRUMENTATION ...............................................................................................................35 5.2.4 DERIVATIZATION...................................................................................................................38 5.2.5 QUANTIFICATION ..................................................................................................................39 5.2.6 NMR .....................................................................................................................................40
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