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Titel:Molecular biological and biochemical investigations of prenyltransferases from different Aspergillus species
Autor:Pockrandt, Daniel
Weitere Beteiligte: Li, Shu-Ming (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0345
URN: urn:nbn:de:hebis:04-z2014-03452
DOI: https://doi.org/10.17192/z2014.0345
DDC:570 Biowissenschaften, Biologie
Titel(trans.):Molekularbiologische und biochemische Untersuchungen zu Prenyltransferasen aus verschiedenen Aspergillus Arten
Publikationsdatum:2014-06-18
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Prenyltransferasen, Aspergillus, Aspergillus, Prenyltransferases

Summary:
Prenylated aromatic compounds are widely distributed in nature and many of these compounds display interesting biological and pharmaceutical activities. The transfer of prenyl moieties to aromatic substrates is catalysed by aromatic prenyltransferases, and the multitude of possibilities for attachment of these moieties gives rise to a large structural diversity. Investigation of the functions of aromatic prenyltransferases would therefore help to elucidate the biosynthetic pathways of those natural compounds in the producing organism, as well as the applicability of these enzymes for chemoenzymatic synthesis of biologically active compounds for pharmaceutical purposes. Four putative prenyltransferase genes of the dimethylallyltryptophan synthase (DMATS) superfamily from Aspergillus nidulans (A. nidulans) were investigated as one part of this thesis. The genes xptA, xptB, ANID_10289 and ANID_11080 were cloned, and the two putative xanthone prenyltransferase genes xptA and xptB were overexpressed in Escherichia coli (E. coli). Both recombinant prenyltransferases were purified to near homogeneity using affinity chromatography with Ni-NTA and investigated biochemically. In this thesis, the enzyme XptB was confirmed to function as a xanthone prenyltransferase, catalysing a regiospecific Oprenylation of several xanthones. The enzyme products were isolated on high performance liquid chromatography (HPLC) and analysed by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). Another previously postulated substrate, the benzophenone arugosin H, was not accepted by XptB under the tested conditions. No enzyme activity was detected for the second enzyme XptA with postulated or potential substrates. Reports of the enzyme VrtC from Penicillium aethiopicum (P. aethiopicum) implicated that some members of the DMATS superfamily might not be restricted to the usual prenyl donor dimethylallyl diphosphate (DMAPP, C5-unit). VrtC was shown as the first known member of the DMATS prenyltransferases, which accepts geranyl diphosphate (GPP, C10-unit), but not DMAPP, for prenylation of a naphthacenedione substrate. Therefore, the acceptance of prenyl donors, such as GPP and farnesyl diphosphate (FPP, C15-unit), was investigated in this thesis with the prenyltransferases 7-DMATS and CdpNPT, both from Aspergillus fumigatus (A. fumigatus), as well as CdpC3PT and AnaPT, both from Neosartorya fischeri (N. fischeri). It was found that AnaPT accepted, in addition to DMAPP, also GPP as prenyl donor. Furthermore, a shift of the prenylation position was observed. Instead of a reverse C3α-prenylation with DMAPP, C6- and C7-geranylations of tryptophan-containing cyclic dipeptides with GPP were demonstrated in this thesis. This was the first report of the acceptance of both DMAPP and GPP by a member of the DMATS superfamily. The observed shift of the prenylation position by changing the prenyl donor expands the applicability of AnaPT for the production of prenylated compounds. As last part of this thesis, the putative prenyltransferase genes AO090102000322, AO090701000600 and AO090020000527 from Aspergillus oryzae (A. oryzae) were cloned. The recombinant protein BAE61387, encoded by AO090102000322, was successfully overproduced and purified from E. coli. Analysis of neighbouring genes in the genome of A. oryzae revealed no backbone genes for the biosynthesis of a possible natural substrate of BAE61387. The enzyme BAE61387 was therefore incubated with a large number of compounds that are known substrates of enzymes from the DMATS superfamily. Activity was clearly observed in incubation mixtures with hydroxynaphthalenes. Interestingly, these unnatural substrates, which are accepted by several members of this enzyme class, were accepted by BAE61387 in the presence of all three prenyl donors DMAPP, GPP and FPP. The acceptance of all these prenyl donors for regiospecific C-prenylations of hydroxynaphthalenes has never been shown for a member of this enzyme superfamily prior to this work.

Zusammenfassung:
Prenylierte aromatische Verbindungen sind in der Natur weit verbreitet und viele dieser Stoffe besitzten interessante biologische und pharmazeutische Aktivitäten. Die Übertragung der Prenylreste auf aromatische Substrate wird durch aromatische Prenyltransferasen katalysiert und die Vielzahl der Verknüpfungsmöglichkeiten der Prenylreste ermöglicht eine hohe strukturelle Diversität prenylierter Naturstoffe. Untersuchungen zur Funktion von aromatischen Prenyltransferasen geben einen Einblick in die Biosynthesewege dieser Naturstoffe und bieten diese Enzyme als Werkzeuge in der chemoenzymatischen Herstellung von biologisch aktiven Substanzen für pharmazeutische Anwendungen an. Vier putative Prenyltransferasegene der Dimethylallyltryptophan Synthase (DMATS) Superfamilie aus Aspergillus nidulans (A. nidulans) wurden als ein Teil der vorliegenden Arbeit untersucht. Die Gene xptA, xptB, ANID_10289 und ANID_11080 wurden kloniert, und die beiden putativen Xanthon-Prenyltransferasegene xptA und xptB wurden in Escherichia coli (E. coli) überexprimiert. Die rekombinanten Enzyme wurden mittels Affinitätschromatographie mit Ni-NTA aufgereinigt und biochemisch im Hinblick auf ihre Enzymaktivität und Substratspezifität untersucht. In der vorliegenden Arbeit konnte das Enzym XptB als Xanthon- Prenyltransferase bestätigt werden, welche die regiospezifische O-Prenylierung von einigen Xanthonen katalysiert. Die enzymatischen Produkte wurden mittels high performance liquid chromatography (HPLC) isoliert und mithilfe von Kernresonanzspektroskopie (NMR) und Massenspektrometrie (MS) untersucht. Ein weiteres in der Literatur postuliertes Substrat von XptB, das Benzophenon Arugosin H, wurde unter den getesteten Bedingungen nicht umgesetzt. Für das zweite aufgereinigte Enzym XptA konnte allerdings keine enzymatische Aktivität, weder in Inkubationsansätzen mit dem postulierten Substrat Variecoxanthon A, noch mit anderen potenziellen Substraten nachgewiesen werden. Mit dem Enzym VrtC aus Penicillium aethiopicum (P. aethiopicum) wurde erstmals die Umsetzung einer Naphthacendion-Verbindung mit Geranyldiphosphat (GPP, C10-Einheit) durch eine DMATS-Prenyltransferase beschrieben. Diese Entdeckung führte zu der Annahme, dass nicht alle DMATS-Prenyltransferasen auf den sonst üblichen Prenyldonor Dimethylallyldiphosphat (DMAPP, C5-Einheit) beschränkt sein müssen. In der vorliegenden Arbeit wurden dazu die bekannten Prenyltransferasen 7-DMATS und CdpNPT, beide aus Aspergillus fumigatus (A. fumigatus), sowie CdpC3PT und AnaPT, beide aus Neosartorya fischeri (N. fischeri), auf die Akzeptanz von GPP und Farnesyldiphosphat (FPP, C15-Einheit) untersucht. Von den untersuchten Enzymen konnte für AnaPT, zusätzlich zu DMAPP, eine Umsetzung von Tryptophan-enthaltenden zyklischen Dipeptiden mit GPP nachgewiesen werden. Für sechs zyklische Dipeptide, für welche mit DMAPP zuvor eine reverse C3α- Prenylierung beobachtet wurde, konnte durch die Verwendung von GPP in der vorliegenden Arbeit die Geranylierung durch AnaPT an den Positionen C-6 und C-7 des Indols nachgewiesen werden. Eine Akzeptanz von sowohl DMAPP als auch GPP durch eine DMATSPrenyltransferase wurde somit erstmals demonstriert. Die Akzeptanz von DMAPP und GPP, sowie die beobachtete Verschiebung der Prenylierungsposition durch den Einsatz von Prenyldonoren unterschiedlicher Länge, erhöhen die Nützlichkeit dieses Enzyms zur chemoenzymatischen Synthese prenylierter Verbindungen. Als letzter Teil dieser Arbeit wurden die drei putativen Prenyltransferasegene AO090102000322, AO090701000600 und AO090020000527 aus Aspergillus oryzae (A. oryzae) kloniert. Das putative Produkt BAE61387 von AO090102000322 wurde in E. coli überproduziert und das rekombinante Enzym erfolgreich aufgereinigt. Durch Sequenzanalysen konnten im Genom von A. oryzae in der Nachbarschaft zu AO090102000322 keine Gene identifiziert werden, welche Aufschluss über ein mögliches natürliches Substrat von BAE61387 geben könnten. Das erhaltene Protein wurde daher mit zahlreichen Substraten von bekannten Enzymen der DMATS-Superfamilie inkubiert. Eine enzymatische Aktivität konnte in Inkubationsansätzen mit einigen Hydroxynaphthalin-Derivaten beobachtet werden. Allerdings wurden diese unnatürlichen Substrate, welche von einigen Mitgliedern der DMATSPrenyltransferasen akzeptiert werden, in Gegenwart von DMAPP, GPP und FPP umgesetzt. Die Akzeptanz der drei Prenyldonoren DMAPP, GPP und FPP zur regiospezifischen CPrenylierung von Hydroxynaphthalin-Derivaten durch eine DMATS-Prenyltransferase wurde zuvor noch nicht demonstriert.

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