Publikationsserver der Universitätsbibliothek Marburg
Titel:Untersuchungen zur Lipoinitiation während der nichtribosomalen Synthese von Daptomycin und Surfactin
Autor:Wittmann, Melanie
Weitere Beteiligte: Marahiel, Mohamed A. (Prof. Dr.)
Veröffentlicht:2010
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0476
DOI: https://doi.org/10.17192/z2010.0476
URN: urn:nbn:de:hebis:04-z2010-04769
DDC:540 Chemie
Titel (trans.):Investigations on the Lipoinitiation during the Nonribosomal Synthesis of Daptomycin and Surfactin
Publikationsdatum:2010-08-23
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
NRPS, Daptomycin, Acylation, Daptomycin, Lipoinitiation, Sekundärmetabolit, Acylierung, Acetylierung, Lipoinitiation, Surfactin, Thioesterase II, Surfactin, NRPS

Zusammenfassung:
Die zyklischen Lipopeptid-Antibiotika stellen eine Klasse strukturell verwandter und bioaktiver Oligopeptide dar, welche durch multimodular aufgebaute Enzymkomplexe, den nichtribosomalen Peptidsynthetasen (NRPS) assembliert werden. Essenziell für die antibiotische Aktivität ist die mit dem Peptidrückgrat verbundene Lipid-Einheit, welche einen einzigartigen Wirkmechanismus dieser Verbindungen ermöglicht. Die Modifikation dieser Fettsäure-Komponente ermöglicht somit die Optimierung der pharmakologischen Eigenschaften der Lipopeptid-Antibiotika bezüglich der Bioaktivität, Stabilität sowie der Pharmakokinetik. Das Ziel der vorliegenden Arbeit war die mechanistische Aufklärung der Lipoinitiation des aziden Lipopeptids Daptomycin (Cubicin®) und des Biotensids Surfactin. Dazu sollten mittels bioinformatischer Methoden die für die Acylierung verantwortlichen Proteine identifiziert und in vivo und in vitro charakterisiert werden. Die bioinformatische Genomanalyse des Daptomycin Produzentenstammes Streptomyces roseosporus ermöglichte die Identifizierung der im Daptomycin Biosynthesegencluster codierten Acyl-CoA-Synthetase DptE und des Acyl-Carrier-Proteins (ACP) DptF als putative Lipidierungsmaschinerie. Zur in vitro Charakterisierung wurden diese Enzyme heterolog produziert, isoliert und auf ihre Aktivität und Substratspezifität hin untersucht. Hierbei zeigte sich, dass DptE eine hohe Substrattoleranz aufweist und diverse Fettsäuren als Adenylat aktiviert und auf das kognate ACP DptF transferiert. Kinetische Spezifitätsuntersuchungen bestätigten, dass DptE eine hohe Präferenz für Fettsäuren zeigt, welche auch im natürlichen Daptomycin-Komplex (A21978C-Faktoren) vorkommen. Die Analyse der Transferreaktion mit verschiedenen ACPs zeigte, dass DptE eine hohe Affinität gegenüber DptF aufweist. Im Gegensatz zu Daptomycin konnten im Biosynthesegencluster von Surfactin (Bacillus subtilis MR168) keine Acyl-CoA-Synthetasen identifiziert werden, welche β-Hydroxy-myristinsäure aktivieren und auf das Beladungsmodul (SrfA-M1) übertragen können. Die Analyse des annotierten B. subtilis Genoms zeigte vier putative Proteine (LcfA, YhfL, YhfT, YngI) mit Sequenzhomologien zu Acyl-CoA-Synthetasen, welche nicht im Surfactin-Operon codiert vorlagen. Zur biochemischen Charakterisierung wurden diese heterolog produziert, isoliert und biochemisch untersucht. Hierbei zeigte sich, dass LcfA und YhfL die native β-Hydroxy-myristinsäure als CoA-Thioester aktivieren, wohingegen YhfT das Substrat ausschließlich als Adenylat aktiviert. Die Generierung von lcfA-, yhfT- und yngI-Deletionsmutanten in B. subtilis bestätigten die Beteiligung der identifizierten Enzyme an der Acylierung von Surfactin. So führte die gleichzeitige Deletion der drei putativen Acyl-CoA-Synthetasen zu einer Reduktion der Surfactin-Produktion um 98%. Zukünftige Komplementierungsstudien werden eine detailliertere Analyse der Lipidierungs- und Initiierungsreaktion während der Surfactin-Assemblierung ermöglichen. Die in dieser Arbeit durchgeführten Untersuchungen zur Lipidierung der klinisch relevanten zyklischen Lipopeptide Daptomycin und Surfactin resultieren in der Postulierung zweier unterschiedlicher Acylierungsstrategien während der nichtribosomalen Synthese von Oligopeptiden. Die Umsetzung der hierdurch gewonnenen Erkenntnisse sollte in Zukunft die Generierung von Daptomycin- und Surfactin-Derivaten mit optimierter Bioaktivität durch metabolic engineering ermöglichen.

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