Publikationsserver der Universitätsbibliothek Marburg
Titel:Biochemische und strukturelle Untersuchungen der Biosynthese unnatürlicher Aminosäuren als Bausteine nicht-ribosomaler Peptide
Autor:Helmetag, Verena
Weitere Beteiligte: Marahiel, Mohamed A. (Prof. Dr.)
Veröffentlicht:2009
URI:https://archiv.ub.uni-marburg.de/diss/z2010/0061
URN: urn:nbn:de:hebis:04-z2010-00616
DOI: https://doi.org/10.17192/z2010.0061
DDC: Chemie
Titel (trans.):Biochemical and Structural Investigations of the Biosynthesis of Non-Proteinogenic Amino Acids as Building Blocks of Non-Ribosomal Peptides
Publikationsdatum:2010-03-29
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Kristallstrukturanalyse, Aminosäuren, Hydroxylierung, non-ribosomal peptide synthesis, Modifikation <Biochemie>, Sekundärmetabolit, Nicht-ribosomale Peptidsynthese, Cß- and Nδ-modifications, Methylierung, nicht-proteinogene Aminosäuren, non-proteinogenic amino acids, Antibiotikum, Modifikationsenzyme, Cß- und Nδ-Modifikationen, Tailoring enzymes, antibiotics

Zusammenfassung:
Nicht-ribosomal synthetisierte Peptide weisen eine hohe strukturelle Vielfalt auf, die durch die Anwesenheit vieler nicht-proteinogener Bausteine hervorgerufen wird. Es wurde gezeigt, dass diese Bausteine oft essentiell für die Bioaktivität des jeweiligen Naturstoffs sind, jedoch ist die Biosynthese vieler dieser Bausteine weitestgehend nicht verstanden. Die hier vorgestellte Arbeit beschäftigt sich mit drei chemisch anspruchsvollen Modifikations-reaktionen an freien Aminosäuren, die effektiv durch so genannte Modifikationsenzyme durchgeführt werden. Die ungewöhnlichen, modifizierten Aminosäuren dienen dann als Synthesebausteine für die nicht-ribosomale Peptidsynthese. Im ersten Teil der Arbeit wird der Biosyntheseweg von Nδ-hydroxylierten und Nδ formylierten Ornithin-Resten in vitro untersucht. Diese Bausteine werden für die Biosynthese des Tris-Hydroxamat-Siderophors Coelichelin benötigt, in dem sie für die Komplexierung von Eisen(III)-Ionen verantwortlich sind. Für die Untersuchungen wurden die Flavin-abhängige Monooxygenase CchB und die Formyltransferase CchA aus Streptomyces coelicolor rekombinant hergestellt und biochemisch charakterisiert. Für CchB konnte, im Gegensatz zu CchA, Aktivität in vitro nachgewiesen werden. Da das Enzym ausschließlich freies L-Ornithin hydroxylierte, konnte gezeigt werden, dass diese Hydroxylierungsreaktion den ersten Schritt in der Biosynthese von Coelichelin darstellt und somit essentiell für dessen Produktion ist. Der zweite Teil der Arbeit beschäftigt sich mit der stereospezifischen Cβ-Hydroxylierung von L Arginin, die von einem organisch-synthetischen Standpunkt aus betrachtet sehr aufwendig ist. Diese Reaktion wird von der nicht-Häm Eisen(II)- und α-Ketoglutarat-abhängigen Mono-oxygenase VioC aus Streptomyces vinaceus katalysiert und resultiert in dem Baustein erythro-β-Hydroxy-Arginin. Dieser wird nach einer weiteren Modifikationsreaktion in das Peptidgerüst des Antibiotikums Viomycin eingebaut. Interessanterweise katalysiert der Großteil von nicht-Häm Eisen(II)-/α-Ketoglutarat-abhängigen Monooxygenasen die Bildung von threo Diastereomeren. Neben der biochemischen Charakterisierung von VioC wurde in dieser Arbeit auch die Lösung der Kristallstruktur der Monooxygenase durchgeführt. Anhand der erhaltenen Daten konnten die unerwartete Substrattoleranz von VioC und die für diese Enzymklasse ungewöhnliche erythro Stereochemie erklärt werden. Eine weitere Cβ-Funktionalisierung einer freien Aminosäure wird im dritten Teil dieser Arbeit untersucht. Der nicht-proteinogene Vorläuferbaustein (2S,3S)-β-Methyl-Phenylalanin, dessen chemische Synthese sehr anspruchsvoll ist, wird in das Glykopeptid-Antibiotikum Mannopeptimycin in Streptomyces hygroscopicus eingebaut. Um den Biosyntheseweg zu untersuchen, wurde die S-Adenosylmethionin-abhängige Methyltransferase MppJ in vitro auf Aktivität getestet. Es konnte gezeigt werden, dass nicht wie erwartet Phenylalanin direkt methyliert wird, sondern dass die α-Ketosäure Phenylpyruvat von MppJ zu β-Methyl-Phenylpyruvat konvertiert wird. Eine anschließende Transaminierungsreaktion mit der Pyridoxal-5’-Phosphat-abhängigen Aminotransferase IlvE aus dem Primärmetabolismus von Streptomyces coelicolor resultierte in der Bildung der beiden Diastereomere (2S,3S)- und (2S,3R)-β-Methyl-Phenylalanin. Es konnte nicht endgültig gezeigt werden, ob die MppJ-katalysierte Methylierungsreaktion stereospezifisch verläuft oder nicht. Allerdings wurden in dieser Arbeit neue Erkenntnisse bezüglich der Cβ-Funktionalisierung von Phenylalanin bzw. Phenylpyruvat erhalten.

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