Publikationsserver der Universitätsbibliothek Marburg

Titel:Biochemical Investigations on Microbial Prenyltransferases in the Presence of DMAPP Analogues
Autor:Liebhold, Mike Patrick
Weitere Beteiligte: Li, Shu-Ming (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0698
DOI: https://doi.org/10.17192/z2014.0698
URN: urn:nbn:de:hebis:04-z2014-06982
DDC: Medizin, Gesundheit
Titel(trans.):Biochemische Untersuchungen an mikrobiellen Prenyltransferasen in Anwesenheit von DMAPP-Analoga
Publikationsdatum:2015-05-28
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Chemical Synthesis, Streptomycetaceae, Dimethylallyl-Transferase <Dimethylallyl-trans-Transferase>, DMAPP Analogues, Schlauchpilze, Enzymkatalyse, Prenyltransferases

Summary:
Plants, bacteria and fungi provide a plethora of diverse structures derived from the primary as well as the secondary metabolism. Representative substances from secondary metabolite pathways are flavonoids, coumarins, xanthones and indole alkaloids. Although not necessary for the growth and reproduction of the respective organisms, nevertheless these compounds give them an advantage over other organisms in the form of, e.g. attractants or protection agents against natural enemies as well as competitors. The attachment of isoprene units (n  C-5) such as dimethylallyl, geranyl or farnesyl moieties to aromatic secondary metabolites as backbones is a further step in the broad diversification of these compounds. Enzymes of the class of prenyltransferases accomplish this prenyl transfer reaction in nature. The prenylated natural products often exhibit strong pharmacological activities in contrast to their substrates. Therefore, prenylated compounds represent interesting targets for drug development. Investigations on alternative alkyl residues transferable via prenyltransferases, i.e. prenyl diphosphate analogues, could have the potential to play an important role in the understanding of the catalytic mechanism of these enzymes as well as in the finding process of new drugs. As the first project in this thesis, the acceptance of four chemically synthesized alkyl and allyl diphosphates in the presence of three L-tryptophan prenyltransferases (FgaPT2, 5 DMATS, 7 DMATS) was elucidated. Retaining the double bond in β position and performing alterations on the methyl groups of the allyl residue led to regular alkylated products and thereby showed successful utilization of DMAPP analogues. However, depending on the DMAPP analogue, the regiospecificity of the applied prenyltransferases was shifted partially or completely. Furthermore, the enzymes did not catalyze the transfer reaction of alkyl diphosphates onto the L tryptophan scaffold, if no double bond was present or if it was relocated to  position compared to DMAPP. Subsequently, the behavior of cyclic dipeptide prenyltransferases (AnaPT, CdpNPT, CdpC3PT, FtmPT1, BrePT) towards the unnatural alkyl and allyl donors was examined. The cyclic dipeptide prenyltransferases also used the unsaturated DMAPP analogues resulting in the formation of multiple products. Regardless of the prenylation position and orientation for the prenyl attachment (C 2 or C 3; regular or reverse) in the presence of DMAPP, the enzymatic reactions with both DMAPP analogues, i.e. MAPP and 2-pentenyl-PP, yielded a mixture of C2 reverse as well as C3 reverse alkylated diastereomers in different ratios depending on the donor and used enzyme. After the successful alkylation of L tryptophan and tryptophan-containing cyclic dipeptides utilizing simple unnatural allyl DMAPP analogues, the acceptance of the structurally more complex DMAPP analogue benzyl diphosphate was tested. Preliminary investigations showed the successful usage of this benzyl donor by several L tryptophan and cyclic dipeptide prenyltransferases, whereas FgaPT2 showed the highest activity. FgaPT2 also displayed a remarkable promiscuity using tryptophan analogues as substrates and catalyzing a highly regiospecific C5 benzylation. Consequently, the usage of benzyl diphosphate instead of dimethylallyl diphosphate results in a complete shift of the prenylation position from C 4 to C 5. To complete our findings regarding the acceptance of unnatural alkyl and benzyl analogues by prenyltransferases, several tryptophan C5-, C6- and C7-prenylating enzymes of fungal and bacterial origin have been assayed with the three analogues. Depending on the enzyme used, one to four products could be identified from the incubation mixtures. The predominant products were regular C6-alkylated or C6-benzylated derivatives in all cases. Therefore, for the tested tryptophan C5-, C6- and C7-prenylating enzymes, C-6 seemed to be the preferred position for attachment of the alkyl or benzyl moiety. The results obtained during this thesis show that allyl as well as benzyl analogues of DMAPP are potential alternatives for chemoenzymatic FriedelCrafts alkylations of simple indole derivatives and tryptophan-containing cyclic dipeptides and could be used for the production of alkylated compounds.

Zusammenfassung:
Pflanzen, Bakterien und Pilze weisen eine Fülle an unterschiedlichen Strukturen sowohl aus dem Primär- als auch aus dem Sekundärstoffwechsel auf. Vertreter, der aus dem Sekundärstoffwechsel stammenden Substanzen, sind unter anderem Flavonoide, Coumarine, Xanthone und Indol-Alkaloide. Wenngleich sie nicht essenziell für das Wachstum und die Reproduktion der entsprechenden Organismen sind, verschaffen diese Stoffe ihren Produzenten dennoch einen Vorteil gegenüber anderen Organismen, zum Beispiel in Form von Lockstoffen, als Fraßschutz sowie als Abwehrstoffe gegen Konkurrenten. Das Anbringen von Isopren Einheiten (n  C5) wie zum Beispiel Dimethylallyl-, Geranyl- oder Farnesyl Gruppen an diese Grundstrukturen aus dem Sekundärstoffwechsel ist ein weiterer Schritt zur breiten Differenzierung dieser Stoffe. In der Natur bewerkstelligen Prenyltransferasen diese Prenylierungsreaktion. Prenylierte Naturstoffe weisen, im Gegensatz zu ihren Substraten, oftmals starke pharmakologische Wirkungen auf. Daher stellen sie interessante Moleküle für die Entwicklung von Arzneistoffen dar. Untersuchungen an, mit Hilfe von Prenyltransferasen übertragbaren, alternativen Alkyl Resten, sogenannten Prenyl-Diphosphat Analogen, könnten eine wichtige Rolle beim Verstehen der katalytischen Mechanismen dieser Enzyme und ebenso bei der Entwicklung neuer Arzneistoffe spielen. Zu Beginn dieser Dissertation wurde die Akzeptanz vier chemisch synthetisierter Alkyl- und Allyl Diphosphate durch drei L-Tryptophan-Prenyltransferasen (FgaPT2, 5 DMATS, 7 DMATS) aufgeklärt. Wurde die Doppelbindung an β Position beibehalten und nur die Methylgruppen verändert, so führte dies zur Bildung von regulär alkylierten Produkten und zeigten damit die erfolgreiche Anwendung von DMAPP-Analoga. Es wurde jedoch eine teilweise bzw. vollständige Verschiebung der Regiospezifität der verwendeten Prenyltransferasen beobachtet, abhängig vom eingesetzten DMAPP Analog. Die Enzyme katalysierten hingegen nicht die Übertragung von Alkyl-Diphosphaten mit fehlender oder bzw. nach  Position verschobener Doppelbindung. Weiterhin wurde das Verhalten zyklischer Dipeptid-Prenyltransferasen (AnaPT, CdpNPT, CdpC3PT, FtmPT1, BrePT) gegenüber unatürlichen Alkyl- und Allyl Donoren untersucht. Die zyklischen Dipeptid-Prenyltransferasen akzeptierten ebenfalls die ungesättigten DMAPP Analoga MAPP und 2-pentenyl-PP und führten zur Bildung mehrerer Produkte. Ungeachtet der Position und Ausrichtung des Prenyl-Restes (C-2 oder C 3) in Anwesenheit von DMAPP, brachten die Reaktionen dieser Enzyme eine Mischung von C2- sowie C3-revers alkylierten Diastereomeren in unterschiedlichen Verhältnissen hervor, abhängig vom gewählten Donor sowie Enzym. Nach der erfolgreichen Alkylierung von L Tryptophan sowie Tryptophan-haltigen zyklischen Dipeptiden mittels einfacher allylischer DMAPP-Analoga wurde die Akzeptanz eines strukturell komplexeren DMAPP-Analogons (Benzyl-Diphosphat) getestet. Vorangegangene Untersuchungen zeigten, dass mehrere L Tryptophan- sowie zyklische Dipeptid-Prenyltransferasen diesen Benzyl-Donor akzeptierten, wobei FgaPT2 den höchsten Umsatz verzeichnete. FgaPT2 wies außerdem eine breite Substratspezifität auf und nutzte sowohl L Tryptophan als auch verschiedene Derivate hiervon. In diesen Fällen katalysierte diese Prenyltransferase mit hoher Regiospezifität eine C5 Benzylierung, was eine vollständige Verschiebung der Prenylierungposition von Position C-4 darstellt. Um die Untersuchungen bezüglich der Akzeptanz nicht natürlicher Alkyl- sowie Benzyl Analoga abzurunden, wurden verschiedene Enzyme, welche Tryptophan an den Positionen C 5, C-6 oder C-7 prenylieren, aus Pilzen wie auch aus Bakterien zusammen mit den drei DMAPP Analoga inkubiert. Je nach verwendetem Enzym konnten bis zu vier Produkte isoliert werden. In allen Enzymassays war C6-alkyliertes oder benzyliertes L-Tryptophan das Hauptprodukt. Position C-6 des Indolringes wurde somit für die C-5, C-6 oder C-7 prenylierenden Enzyme zur bevorzugten Angriffspunkt für die Übertragung der Alkyl- oder des Benzyl-Restes. Die in dieser Dissertation genannten Ergebnisse zeigen, dass sowohl Allyl- als auch Benzyl Analoga von DMAPP als mögliche Alternativen für chemoenzymatische FriedelCrafts Alkylierungen zur Herstellung unnatürlich alkylierter Substanzen verwendet werden können.

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