Dokument

Zusammenfassung:
Bakterielle Lassopeptide sind ribosomal synthetisierte, bioaktive Peptide, die sich aus 16 bis 21 proteinogenen Aminosäuren zusammensetzen. Sie zeichnen sich durch eine verzweigt-zyklische Primärstruktur aus, die durch einen N-terminalen Makrolaktamring und einen linearen C-Terminus charakterisiert ist. Der C-Terminus ist nicht frei beweglich, sondern durch den makrozyklischen Ring hindurch gefädelt und dabei entweder durch sterische Hinderung voluminöser Aminosäureseitenketten oder kovalent durch Disulfidbindungen verankert. Die daraus resultierende Lassostruktur führt zu einer außerordentlichen Stabilität gegenüber Proteasen, hohen Temperaturen und chemischen Denaturierungsmitteln und begründet in Kombination mit der genetischen Kodierung und bakteriellen Herkunft das steigende Interesse an diesen einzigartig strukturierten Peptiden. In dieser Arbeit wurde ein auf Genomischem Mining basierendes Verfahren zur Identifizierung neuer Lassopeptidbiosynthesecluster in Bakterien entwickelt. Mit Hilfe dieser Strategie konnte ein kryptisches Gencluster im Genom von Burkholderia thailandensis E264 identifiziert und eine Verbindung mit der Masse des postulierten Lassopeptids im Kulturüberstand nachgewiesen werden. Strukturuntersuchungen mittels Massenspektrometrie und NMR-Spektroskopie belegten die Lassostruktur der isolierten Verbindung, die Capistruin genannt wurde. Das 19-AS Lassopeptid, das eine antibakterielle Aktivität gegen Vertreter des pathogenen Burkholderia cepacia-Komplexes zeigte, konnte durch Expression des Genclusters in Escherichia coli heterolog produziert werden. Die anschließende Mutationsanalyse des ribosomalen Vorläuferproteins führte zur Identifizierung von vier Positionen innerhalb der Lassopeptidsequenz, die kritisch für die Reifung des Peptids waren. Innerhalb des Leaderpeptids erwies sich Threonin an der P2-Position der Proteaseschnittstelle als essentiell für die Prozessierung des Vorläufers. Durch eine Stabilitätsanalyse ausgewählter Capistruinvarianten wurden Einblicke in Struktur-Stabilitäts-Beziehungen erhalten und Arg15 als der für die Verankerung des C-Terminus verantwortliche Rest identifiziert. Ferner wurde mit Capistruin R15A/F16A das erste temperatursensitive Lassopeptid generiert, das thermisch in eine verzweigt-zyklische Struktur entfaltet werden kann. Darüber hinaus wurden die zwei verzweigt-zyklischen Peptide BI-32169 und Anantin massenspektrometrisch und NMR-spektroskopisch untersucht. Dabei konnte für beide Peptide die postulierte Lassostruktur bewiesen werden, die aufgrund der Ähnlichkeit ihrer Primärstruktur mit der von Lassopeptiden vermutet worden war. Der Glucagonrezeptorantagonist BI-32169 unterscheidet sich dabei von den bisherigen Lassopeptiden der Klassen I und II und kann daher als Begründer der neuen Klasse III angesehen werden. Die relaxierte Substratspezifität der Biosynthesemaschinerie von Lassopeptiden legte eine Verwendung der stabilen Peptidgerüste zur Präsentation von Pharmakophoren nahe, um die intrinsischen Stabilitätseigenschaften mit den Funktionen bioaktiver Epitope zu kombinieren. Die Konversion des Lassopeptids MccJ25 in einen nanomolaren Inhibitor von avb3 und avb5 Integrinen mit anti-angiogenetischer Wirkung durch die Insertion des Integrinbindungsmotivs RGD in das stabile Peptidrückgrat verdeutlicht dieses bisher ungenutzte Potential lassostrukturierter Peptide. Die Ergebnisse dieser Arbeit liefern einen Einblick in die Struktur, Stabilität und Biosynthese von bakteriellen Lassopeptiden und werden in Zukunft das Genomische Mining nach lassostrukturierten Peptiden erleichtern und damit zur Identifizierung von neuen, alternativen Peptidgerüsten beitragen, die zur Präsentation von bioaktiven Epitopen verwendet werden können.

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