Dokument

Zusammenfassung:
Eisen-Schwefel-Cluster gehören zu den wichtigsten und vielseitigsten Cofaktoren in der Natur. Viele essentielle Stoffwechselwege, wie der Citratzyklus oder die Atmungskette sind direkt abhängig von Eisen-Schwefel-Enzymen. Durch die Toxizität von freiem Eisen und Sulfid sind die Organismen auf eine streng regulierte Biosynthese der Fe/S-Cluster angewiesen. Hierfür haben sich verschiedene Maschinerien entwickelt, die in allen Fällen auf drei essentiellen Kernkomponenten aufbauen: Einem Scaffoldprotein, auf dem der Cluster assembliert wird, eine Cysteindesulfurase zur Mobilisierung von Schwefel aus Cystein und ein Eisendonor, vermutlich ein Homologes von Frataxin. In dieser Arbeit wurden die Kernkomponenten des Eisen-Schwefel-Cluster-Biosynthese-systems von Bacillus subtilis untersucht. Nach der Identifizierung des potentiellen SufCDSUB-Systems durch BLAST-Analyse, wurde durch in vivo Untersuchungen an Deletionsmutanten zunächst das putative Scaffoldprotein SufU identifiziert. Es konnte gezeigt werden, dass eine verringerte Expression von SufU drastische Auswirkungen auf das Wachstum sowie eine reduzierte Aktivität von Eisen-Schwefel-Proteinen in Bacillus subtilis zur Folge hat. Weiterhin konnte in vitro gezeigt werden, dass SufU in der Lage ist, einen Fe/S-Cluster zu binden und diesen auf apo-Fe/S-Proteine zu transferieren. Neben dem Scaffoldprotein wurde die zweite Kernkomponente der Fe/S-Cluster Biosynthese charakterisiert: die Cysteindesulfurase SufS. Hier konnte gezeigt werden, dass SufS nur sehr geringe Aktivität aufweist und erst durch das Scaffoldprotein SufU aktiviert wird. Die Aktivierung von SufS ist dabei sowohl von der Cystein- als auch von der SufU-Konzentration abhängig. Durch weitere kinetische Untersuchungen konnte gezeigt werden, dass der Sulfidtransfer zwischen SufS und SufU einem Ping-Pong Reaktionsmechanismus folgt und Cystein 41 in SufU für den Mechanismus des Sulfidtransfers eine entscheidende Rolle spielt. Abschließend wurde Fra (YdhG) charakterisiert; ein Protein, das stukturhomolog zu humanem Frataxin ist. Eine Fra-Deletionsmutante zeigte einen Phänotyp, der auf eine deutliche Störung des gesamten Eisenhaushalts hindeutet. In vitro konnte gezeigt werden, dass Fra in der Lage ist Eisen zu binden und als Eisendonor für den Fe/S-Cluster Aufbau von SufU zu wirken.

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