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Titel:Biochemical investigations on bacterial and fungal dimethylallyltryptophan synthases
Autor:Winkelblech, Julia
Weitere Beteiligte: Li, Shu-Ming (Prof.Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0790
DOI: https://doi.org/10.17192/z2016.0790
URN: urn:nbn:de:hebis:04-z2016-07906
DDC: Biowissenschaften, Biologie
Titel(trans.):Biochemische Untersuchungen zu bakteriellen und pilzlichen Dimethylallyltryptophan-Synthasen
Publikationsdatum:2016-11-30
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
enantioselectivity, natural products, Stereoselektivität, Homology Modeling, dimethylallyltryptophan synthases, Friedel-Crafts-Reaktion, Regioselektivität, Prenyltransferase, Streptomyces,Biokatalysator, Naturstoff, DMATS, Enzymkinetik, Prenylgruppe, DMAPP, prenyltransferases, regioselectivity

Summary:
Prenyl transfer reactions occur ubiquitously in nature and play an important role in primary and secondary metabolism in all domains of life. Prenylated secondary metabolites including indole alkaloids usually demonstrate improved biological and pharmacological activities and thus makes them to promising candidates for drug discovery and development. Important producers of such bioactive compounds are fungi of ascomycetes and bacteria of actinomycetes. The transfer reactions of a prenyl moiety from prenyl diphosphate, primarily dimethylallyl diphosphate (DMAPP), onto indole derivatives including tryptophan are mainly catalyzed in nature by the members of the dimethylallyltryptophan synthase (DMATS) superfamily. In the last years, remarkable progress has been achieved in their biochemical, molecular biological, and structural characterization, especially for DMATS enzymes from fungi. The major challenge of this thesis is to provide a better understanding of the catalytic features of these enzymes from different origins. Cloning and expression of these genes as well as the subsequent biochemical investigations of the three novel tryptophan prenyltransferases provided several new intriguing features. Initially, two tryptophan C6-prenyltransferases were identified, i.e. 6-DMATSSa from Streptomyces ambofaciens and 6-DMATSSv from Streptomyces violaceusniger. Biochemical investigation on these enzymes revealed a remarkable broad substrate specificity. In addition to a number of indole derivatives also several hydroxynaphthalenes were accepted by 6-DMATSSa and 6-DMATSSv. Moreover, they represent the first examples of tryptophan prenyltransferases that accept both DMAPP and geranyl diphosphate (GPP) as prenyl donors and catalyze the same prenylation positions. Consequently, the studied 6-DMATSs were used for further investigations on the acceptance of unnatural alkyl or benzyl donors. Prior to this study, investigations on this issue are limited to fungal C4- and C5- prenyltransferases. The L-tyrosine prenyltransferase TyrPT with a tryptophan C7-prenyltransferase activity, the two mentioned 6-DMATSs as well as the bacterial 5-DMATSSc (SCO7467) were included in this project. In total, five C5-, C6- and C7-prenytransferases were investigated in the presence of the DMAPP analogs methylallyl (MAPP), 2-pentenyl (2-pentenyl-PP) and benzyl diphosphate (benzyl-PP). The unnatural donors were accepted by all tested enzymes with different relative activities and regioselectivities. C6-alkylated or benzylated derivatives were identified in all the reactions, as unique product of the two 6-DMATSs or as one of the main products of the other enzymes. These results demonstrated a clear preference of the five enzymes for alkylation/benzylation at C-6 of the indole ring in the presence of the unnatural DMAPP derivatives. Furthermore, homology modeling of the 5-DMATS and subsequent docking as well as molecular dynamics studies with DMAPP, MAPP and 2-pentenyl-PP, led to a distance-based explanation of the observed reaction results. Later on, a third tryptophan C6-prenyltransferase 6-DMATSMo from Micromonospora olivasterospora was identified and characterized. The most notable feature of 6-DMATSMo is the high relative activity toward D-tryptophan. This result led to the comparative study on enantioselectivity of the seven DMATS enzymes from fungi and bacteria. The tested prenyltransferases displayed different substrate preferences as well as different regioselectivities toward the L- and D-enantiomers of tryptophan and their methylated derivatives. Interestingly, the bacterial 5-DMATSSc and 6-DMATSMo highly preferred the D-enantiomer of 5-methyltryptophan to the L-enantiomer, although that was the better substrate in all other reactions. In the presence of the racemate, the D-enantiomer reaction was strongly inhibited, which could be explained by the high affinity to the respective L-form as the main reason. Another interesting output of this project is the reduced or even completely changed regioselectivity for the reactions of FgaPT2, 5-DMATSSc, and 7-DMATS with the D-enantiomers of tryptophan or 5-methyltryptophan. Moreover, the observed diprenylation by 5-DMATSSc was the first report on a tryptophan prenyltransferase which catalyzes two successive prenylation steps. In conclusion, identification and characterization of the three new 6-DMATSs from actinomycetes expand our knowledge on bacterial tryptophan prenyltransferases. Furthermore, prenyltransferases including the three 6-DMATSs could serve as valuable biocatalysts in chemoenzymatic synthesis for alkylated compounds with potential biological activities.

Zusammenfassung:
Prenylierungsreaktionen sind in der Natur weit verbreitet und spielen eine wichtige Rolle in dem Primär- und Sekundärmetabolismus aller Lebensformen. Prenylierte Sekundärmetabolite einschließlich Indolalkaloide weisen häufig eine verstärkte biologische und pharmakologische Aktivität auf, wodurch sie vielversprechende Kandidaten für die Arzneistoff-Findung und Entwicklung darstellen. Wichtige Produzenten solcher bioaktiver Substanzen sind Pilze der Askomyzeten und Bakterien der Aktinomyzeten. Die Übertragung eines Prenylrestes meistens von Dimethylallyldiphosphat (DMAPP), auf Indolderivate mitunter Tryptophan werden in der Natur durch Enzyme der Dimethylallyltryptophan-Synthase (DMATS)-Superfamilie katalysiert. Bemerkenswerte Fortschritte wurden in den letzten Jahren in der biochemischen, molekularbiologischen und strukturellen Charakterisierung dieser Enzyme, insbesondere solcher aus Pilzen, erzielt. Die größte Herausforderung dieser Arbeit besteht darin, ein besseres Verständnis über die katalytischen Eigenschaften dieser Enzyme unterschiedlicher Herkunft zu erlangen. Die Klonierung, Expression und die anschließenden biochemischen Untersuchungen drei neuer Tryptophan-Prenyltransferasen offenbarten neue, interessante Eigenschaften. Zunächst wurden mit 6-DMATSSa aus Streptomyces ambofaciens und 6-DMATSSv aus Streptomyces violaceusniger zwei Tryptophan-C6-Prenyltransferasen identifiziert. Die biochemischen Untersuchungen dieser Enzyme ergaben eine breite Substratspezifität. Neben einer Vielzahl an Indolderivaten wurden auch mehrere Hydroxynaphthaline von 6-DMATSSa und 6-DMATSSv akzeptiert. Zudem handelt es sich um die erstmalige Beschreibung für Tryptophan-Prenyltransferasen, die sowohl DMAPP als auch GPP als Prenyldonor akzeptieren und die Prenylierung an derselben Position katalysieren. Folglich stellen die untersuchten 6-DMATS Enzyme interessante Kandidaten für weitere Untersuchungen bezüglich der Akzeptanz von unnatürlichen Alkyl- oder Benzyldonoren dar. Bisherige Studien zu diesem Thema beschränken sich auf die pilzlichen C4- und C5-Prenyltransferasen. Im Rahmen dieses Projektes wurden daher die L-Tyrosin-Prenyltransferase TyrPT mit Tryptophan-C7-Prenyltransferase Aktivität, zwei 6-DMATS sowie die bakterielle 5-DMATSSc (SCO7467) analysiert. Hierzu wurde das Verhalten der C5-, C6- und C7-Prenytransferasen in Gegenwart der unnatürlichen Prenyldonoren Methylallyl- (MAPP), 2-Pentenyl (2-Pentenyl-PP) oder Benzyldiphosphat (Benzyl-PP) untersucht. Diese DMAPP-Analoga wurden von allen getesteten Enzymen mit unterschiedlichen, relativen Aktivitäten und Regioselektivitäten akzeptiert. C6-alkylierte/benzylierte Derivate wurden in allen Reaktionen identifiziert, entweder als einzelnes Produkt der beiden 6-DMATS oder als eines der Hauptprodukte der anderen Enzyme. Diese Ergebnisse weisen auf eine deutliche Präferenz der fünf Enzyme für die Alkylierung/Benzylierung an C-6 des Indolrings in Gegenwart der unnatürlichen DMAPP-Derivate hin. Des Weiteren führte das „homology modeling“ der 5-DMATS und anschließende „docking“- sowie „molecular dynamics“-Studien mit DMAPP, MAPP und 2-Pentenyl-PP zu einer distanzbasierten Erklärung für die beobachteten Reaktionsergebnisse. Später wurde mit 6-DMATSMo aus Micromonospora olivasterospora eine dritte Tryptophan-C6-Prenyltransferase identifiziert und charakterisiert. Das auffälligste Merkmal der 6-DMATSMo ist die hohe relative Aktivität gegenüber D-Tryptophan. Dieses Resultat führte zu der vergleichenden Studie über die Enantioselektivität von sieben DMATS-Enzymen aus Pilzen und Bakterien. Für die verschiedenen Prenyltransferasen wurden unterschiedliche Substratpräferenzen sowie eine unterschiedliche Regioselektivität bezüglich der L- und D-Enantiomere von Tryptophan und deren methylierten Derivaten festgestellt. Interessanterweise bevorzugten die bakteriellen 5-DMATSSc und 6-DMATSMo das D-Enantiomer von 5-Methyltryptophan gegenüber dem L-Enantiomer, was in allen anderen Reaktionen das bessere Substrat darstellte. In Gegenwart des Racemats, führt die hohe Affinität zur L-Form zur Hemmung der D-Enantiomer-Reaktion. Weiterhin konnte eine reduzierte oder sogar grundlegend veränderte Regioselektivität der Reaktion von FgaPT2, 5-DMATSSc und 7-DMATS mit dem D-Enantiomer von Tryptophan und 5-Methyltryptophan beobachtet werden. Außerdem konnte mit 5-DMATSSc erstmals eine Tryptophan-Prenyltransferase beschrieben werden, die eine Diprenylierung in einem sukzessiven Reaktionsmechanismus katalysiert. Zusammenfassend lässt sich sagen, dass die Identifizierung und Charakterisierung drei neuer 6-DMATS aus Aktinomyzeten zu einem besseren Verständnis bakterieller Tryptophan-Prenyltransferasen führen. Auf Grund der besonderen Eigenschaften untersuchter Prenyltransferasen ergibt sich schließlich die Möglichkeit, mittels neuer Biokatalysatoren das Repertoire alkylierter, potenziell aktiver Substanzen zu erweitern.

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