Publikationsserver der Universitätsbibliothek Marburg

Titel: Ribosome-Independent Biosynthesis of Peptide Natural Products: Nonribosomal Peptide Synthetases and Cyclodipeptide Synthases
Autor: Gießen, Tobias
Weitere Beteiligte: Marahiel, Mohamed A. (Prof. Dr.)
Veröffentlicht: 2013
URI: https://archiv.ub.uni-marburg.de/diss/z2013/0411
DOI: https://doi.org/10.17192/z2013.0411
URN: urn:nbn:de:hebis:04-z2013-04115
DDC: Chemie
Titel(trans.): Ribosom-unabhängige Biosynthese von peptidischen Naturstoffen: Nichtribosomale Peptidsynthetasen und Cyclodipeptidsynthasen
Publikationsdatum: 2014-02-24
Lizenz: https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
nonribosomal peptide synthetases, Molekularbiologie, Ribosom-unabhängige Peptidsynthese, Cyclodipeptide, Peptide, Nichtribosomale Peptide, diketopiperazines, cyclodipeptide synthases, Biochemie, Nonribosomal peptides, Antibiotikum, Diketopiperazine, Naturstoffchemie, Synthetische Biologie

Summary:
Bioactive peptide natural products continue to play an important role in modern medicine since many of them represent last-resort treatments for a variety of life threatening diseases. A large fraction of those peptides are generated via ribosome-independent templated and non-templated biosynthetic pathways. Oftentimes the structural complexity of those peptides has prevented their synthesis and diversification through purely synthetic means. New approaches build on detailed knowledge about the respective biosynthetic pathways have been envisaged where fermentative in vivo or chemoenzymatic strategies are used to generate highly modified peptide natural products. To work towards this vision two templated and two non-templated biosynthetic pathways have been investigated. Both their abilities to generate particular peptide scaffolds and to subsequently decorate a given peptide backbone through the action of dedicated modification enzymes have been explored. The two templated NRPS-dependent pathways studied are the biosynthetic systems of the antitumor-antibiotic sibiromycin and the newly discovered siderophore mirubactin. The origin of the highly substituted anthranilate moiety found in sibiromycin was investigated. The pathway was shown to consist of four steps starting from the known metabolite 3-hydroxykynurenine using detailed in vitro analyses. Initially, the SAM-dependent methyltransferase SibL converts its substrate to the 4-methyl derivative, followed by hydrolysis through the PLP-dependent kynureninase SibQ leading to 3-hydroxy-4-methylanthranilic acid (3H4MAA) formation. Then the NRPS didomain SibE activates 3H4MAA and tethers it to its thiolation domain, where it then serves as the hydroxylation substrate for the FAD/NADH-dependent hydroxylase SibG, yielding the fully substituted anthranilate moiety found in sibiromycin. The siderophore mirubactin was discovered and purified from Actinosynnema mirum through cultivation under iron-limited conditions followed by activity-guided isolation. Structure elucidation was accomplished through a combination of spectroscopic, mass spectrometric and derivatization methods. Bioinformatic analyses coupled with in vitro characterization of its biosynthetic machinery, was used to identify the mirubactin gene cluster. A biosynthetic assembly route could be proposed comprising the iterative use of a stand-alone carrier-protein-bound substrate (MrbD) and the formation of an unusual O-acyl hydroxamic acid ester bond through a C-terminal condensation domain (MrbJ). In addition, two non-templated CDPS-dependent pathways responsible for nocazine biosynthesis and the generation of singly and doubly methylated ditryptophan diketopiperazines (DKPs) have been investigated. The first nocazine gene cluster could be identified through bioinformatic analyses and the biosynthetic pathway leading to the two nocazine family members nocazine E and XR334 could be elucidated through in vivo and in vitro studies. DKP-formation is carried out by a CDPS (Ndas_1148) that shows an unknown product profile forming cyclo(L-Phe-L-Tyr) and cyclo(L-Phe-L-Phe) as its main products. Tailoring of the DKP-scaffold is achieved through the combined and combinatorial action of a cyclic dipeptide oxidase (Ndas_1146/1147) and two distinct SAM-dependent O-/N-methyltransferases (Ndas_1145 and Ndas_1149). A CDPS gene cluster responsible for the formation of methylated ditryptophan DKPs was identified in A. mirum through bioinformatic genome analysis. The assembly pathway was investigated through in vivo and in vitro studies. Initially, the highly specific CDPS Amir_4627 catalyzes the formation of a formerly unknown CDPS product, namely cyclo(L-Trp-L-Trp) followed by the methylation of one or both DKP-ring nitrogens through the action of the SAM-dependent N-methyltransferase Amir_4628 generating singly and doubly methylated ditryptophan DKPs.

Zusammenfassung:
Bioaktive Peptid-Naturstoffe spielen weiterhin eine wichtige Rolle in der modernen Medizin, wo sie oftmals als letzte Option bei schweren, lebensbedrohlichen Erkrankungen eingesetzt werden. Ein großer Teil dieser Peptide wird in der Natur, unabhängig vom Ribosom, durch Templat-abhängige und Templat-unabhängige sekundäre Stoffwechselwege synthetisiert. Oftmals sind diese strukturell komplexen Peptid-Naturstoffe nicht durch rein synthetische Ansätze zugänglich. Deshalb wurde damit begonnen neue Ansätze für in vivo Fermentationsprozesse, sowie chemoenzymatische Strategien zur Synthese und Diversifikation von Peptid-Naturstoffen zu entwickeln. Diese Ansätze fußen auf einem vertieften Verständnis der zugrundeliegenden biosynthetischen Stoffwechselwege. In dieser Arbeit wurden aus diesem Grund jeweils zwei Templat-abhängige und Templat-unabhängige Biosyntheserouten eingehend untersucht. Hierbei standen sowohl die Mechanismen, welche zur Synthese eines bestimmten Peptidgerüsts führen, sowie die zugehörigen Modifizierungsstrategien, die das assemblierte Peptid weiter dekorieren, im Fokus. Bei den beiden untersuchten Templat-abhängigen NRPS-Biosynthesewegen handelt es sich um die Assemblierungsrouten des Antitumor-Antibiotikums Sibiromycin und des neu identifizierten Siderophors Mirubactin. Es wurde durch detaillierte in vitro Studien gezeigt, dass die ungewöhnlich substituierte Anthranilsäure-Gruppe des Sibiromycins durch vier biosynthetische Schritte generiert wird. Ausgehend von 3-Hydroxykynurenin wird durch die SAM-abhängige Methyltransferase SibL eine Methylierung an der 4-Position eingeführt. Die PLP-abhängige Kynureninase SibQ erzeugt anschließend 3-Hydroxy-4-methylanthranilsäure (3H4MAA) durch Hydrolyse. Dieses Intermediat dient nun als Substrate für die NRPS SibE, welche es aktiviert und kovalent an seine Thiolierungsdomäne bindet. Abschließend wird die vollständig modifizierte Anthranilsäure-Gruppe durch online-Hydroxylierung, katalysiert durch die FAD/NADH-abhängige Hydroxylase SibG, gebildet. Das vormals unbekannte Siderophor Mirubactin konnte aus Actinosynnema mirum durch Kultivierung unter Eisen-limitierten Bedingungen, gefolgt von Aktivitäts-geleiteter Aufreinigung, isoliert werden. Durch eine Kombination an spektroskopischen, massenspektrometrischen und Derivatisierungs-Methoden, konnte die Struktur von Mirubactin aufgeklärt werden. Durch bioinformatische Analysen und in vitro Untersuchungen der biosynthetischen Maschinerie konnte der Mirubactin Gencluster identifiziert werden. Es konnte eine Biosyntheseroute postuliert werden, welche die iterative Verwendung eines an eine Thiolierungsdomäne gebundenen Substrats (MrbD), sowie die Bildung eines ungewöhnlichen O-Acylhydroxamsäureesters durch eine C-terminale Kondensationsdomäne (MrbJ), enthält. Zusätzlich wurden zwei Templat-unabhnägige CDPS-Biosynthesewege untersucht, die für die Synthese der Nocazine und die Generierung von modifizierten Ditryptophan-Diketopiperazinen (DKPs) zuständig sind. Mittels bioinformatischer Analysen konnte der erste Nocazine-Gencluster identifiziert werden. Durch in vivo und in vitro Studien konnte die gesamte Biosyntheseroute von Nocazine E und XR334 aufgeklärt werden. Die DKP-Bildung wird durch die CDPS Ndas_1148 katalysiert, welche ein neues Produktprofil aufweist bei dem cyclo(L-Phe-L-Tyr) und cyclo(L-Phe-L-Phe) die beiden Hauptprodukte darstellen. Weitere Modifikation des DKP-Gerüsts wird anschließend durch kombinatorischen Gebrauch einer Cyclodipeptidoxidase (Ndas_1146/1147) sowie zweier SAM-abhängiger O-/N-Methyltransferasen (Ndas_1145 und Ndas_1149) erreicht. Ein CDPS-Gencluster, zuständig für die Biosynthese von methylierten Ditryptophan-DKPs, konnte durch Genomanalyse von A. mirum identifiziert werden. Der Biosyntheseweg wurde durch in vivo und in vitro Untersuchungen aufgeklärt. Zu Beginn katalysiert die hoch spezifische CDPS Amir_4627 die Bildung des vormals unbekannten CDPS-Produkts cyclo(L-Trp-L-Trp). Nun methyliert die SAM-abhängige N-Methyltransferase Amir_4628 entweder einen oder beide Ring-Stickstoffe des DKP-Gerüsts und bildet somit die einfach- oder doppelt-methylierten Ditryptophan-DKP Produkte.

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