Publikationsserver der Universitätsbibliothek Marburg

Titel:Molecular biological and biochemical investigations on the biosynthetic enzymes of prenylated indole alkaloids from fungi
Autor:Yu, Xia
Weitere Beteiligte: Li, Shu-Ming (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0389
URN: urn:nbn:de:hebis:04-z2013-03897
DOI: https://doi.org/10.17192/z2013.0389
DDC: Biowissenschaften, Biologie
Titel(trans.):Molekularbiologische und biochemische Untersuchungen zu Enzymen in der Biosynthese von prenylierten Indolalkaloiden aus Pilzen
Publikationsdatum:2013-08-14
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
indole prenyltransferase, enzyme catalysis, Dimethylallyl-Transferase <Dimethylallyl-trans-Transferase>, prenylated derivative, Katalyse, Indolalkaloide, biosynthesis

Summary:
Prenylated indole alkaloids are widely distributed in plants, fungi and bacteria, especially in the family of Clavicipitaceae and Trichocomaceae of Ascomycota, and commonly exhibit interesting biological and pharmaceutical activities. In the biosynthetic pathway of prenylated indole alkaloids, prenylation catalyzed by prenyltransferases contributes significantly to the large structure diversity of these compounds in nature. Investigation on indole prenyltransferases would help to understand the construction of prenylated indole alkaloids in nature and also be useful for structural modification of indole derivatives and other substances to produce analogues of prenylated derivatives. Three indole prenyltransferases belonging to the dimethylallyltryptophan synthase (DMATS) superfamily were biochemically identified and characterized in vitro, including CdpC3PT from Neosartorya fischeri (N. fischeri), BrePT from Aspergillus versicolor (A. versicolor) and 5-DMATS from Aspergillus clavatus (A. clavatus). The responsible genes cdpC3PT and brePT were cloned into expression vector and heterologously expressed in Escherichia coli (E. coli). These works were carried out by Dr. Wen-Bing Yin, Suqin Yin and Qing Wang, respectively. In this thesis, CdpC3PT was confirmed to catalyze the formation of C3-prenylated products with a characteristic 6/5/5/6-fused tetracyclic ring system from tryptophan-containing cyclic dipeptides in one-step reaction. The NotF homologue BrePT showed much higher flexibility towards its aromatic substrates than NotF, and was proven to catalyze the highly regiospecific reverse prenylation at C-2 of the indole nucleus. The cloning of 5-dmats was carried out by Yan Liu. Functional proof of this gene was provided within this thesis by heterologous expression in E. coli and subsequent structure elucidation of enzyme products by mass spectrometry (MS) and nuclear magnetic resonance (NMR) analyses. 5-DMATS established high regiospecific activity to catalyze C5-prenylation on indole derivatives. Given the importance of prenylation in structure diversity and bioactivity enhancement, CdpC3PT, BrePT, 5-DMATS and other known prenyltransferases of the DMATS superfamily were applied for the chemoenzymatic synthesis of prenylated compounds. By using AnaPT, CdpC3PT and CdpNPT, eight and six stereoisomers of cis-configured prenylated pyrroloindoline diketopiperazines from cyclo-Trp-Ala and cyclo-Trp-Pro isomers were produced, respectively. The stereospecificity of AnaPT and CdpC3PT depended mainly on the configuration of tryptophanyl moiety in cyclo-Trp-Ala and cyclo-Trp-Pro isomers, while CdpNPT showed lower stereoselectivity, but higher conversion ability towards most tested substrates. 5-DMATS and FgaPT2 from Aspergillus were used for chemoenzymatic synthesis of prenylated indolocarbazoles. Reconstitution of enzyme activity of 5-DMATS and FgaPT2 in vitro revealed that they catalyzed regiospecific prenylation of indolocarbazoles at the para-position of the indole N-atom. This is the first report for prenylated indolocarbazoles. Subsequently, some indole prenyltransferases of the DMATS superfamily were found to accept also hydroxynaphthalenes and flavonoids, which were substrates for enzymes from the CloQ/NphB group and the UbiA superfamily, respectively. Nine prenylated flavonoids and twenty prenylated hydroxynaphthalenes have been isolated, and their structures were elucidated by MS and NMR analyses. It has been shown that, for an accepted hydroxynaphthalene, different enzymes produced usually the same major prenylated product, i.e. with a regular C-prenyl moiety at para- or ortho-position to a hydroxyl group. For flavonoids accepted by 7-DMATS, C-6 between two hydroxyl groups was the favorable prenylation position. The Michaelis-Menten constants (KM) and turnover numbers (kcat) of some prenyltransferases towards selected hydroxynaphthalenes are comparable to those obtained by using indole derivatives. In addition to indole prenyltransferases, other genes in the biosynthetic cluster of prenylated indole alkaloids were also investigated. A putative O-methyltransferase gene hasC and a putative cytochrome P450 gene hasH involved in the biosynthesis of hexadehydroastechrome (HAS) in Aspergillus fumigatus (A. fumigatus) were cloned into pQE60 and pESC-URA, respectively. Soluble His6-HasC was successfully overproduced in E. coli SG13009 and purified to near homogeneity by Ni-NTA. Constructs for co-expression with the reductase gene NFIA_083630 from N. fischeri in pESC-URA and for expression as His6-tagged protein in pESC-URA were also prepared for the putative cytochrome P450 gene hasH.

Zusammenfassung:
Prenylierte Indolalkaloide sind ubiquitär in Pflanzen, Bakterien und Pilzen verbreitet, vor allem in den Familien Clavicipitaceae und Trichocomaceae der Ascomyceten. Gemeinsam weisen sie interessante biologische und pharmazeutische Aktivitäten auf. Bei der Biosynthese von Indolalkaloiden ist die Prenylierung durch Prenyltransferasen maßgeblich für die hohe Strukturvielfalt dieser Substanzen in der Natur verantwortlich. Biochemische Untersuchungen zu Indolprenyltransferasen können helfen, die Entstehung von prenylierten Indolalkaloiden in der Natur zu verstehen. Außerdem können Indolderivate und anderen Substanzen durch Prenyltransferasen modifiziert werden. Drei Indolprenyltransferasen der Dimethylallyltryptophan Synthase (DMATS) Superfamilie wurden biochemisch identifiziert und in vitro charakterisiert, diese beinhalteten CdpC3PT aus Neosartorya fischeri (N. fischeri), BrePT aus Aspergillus versicolor (A. versicolor) und 5-DMATS aus Aspergillus clavatus (A. clavatus). Die verantwortlichen Gene cdpC3PT und brePT wurden jeweils in einen Expressionsvektor kloniert und heterolog in Escherichia coli (E. coli) exprimiert. Diese Arbeiten wurden von Dr. Wen-Bing Yin, Suqin Yin und Qing Wang durchgeführt. In der vorliegenden Arbeit wurde herausgefunden, dass CdpC3PT die Entstehung von C3-prenylierten Produkten mit einem charakteristischen 6/5/5/6-tetrazyklischen Ringsystem aus tryptophan-haltigen zyklischen Dipeptiden in einem Reaktionsschritt katalysiert. Das NotF-Homolog BrePT zeigte eine sehr viel höhere Flexibilität gegenüber seinen aromatischen Substraten im Vergleich zu NotF. Dabei konnte eine hohe Regiospezifität einer reversen Prenylierung an Position C-2 des Indolrings nachgewiesen werden. Bei der Charakterisierung von 5-DMATS wurde die Klonierung von Yan Liu durchgeführt. Im weiteren Verlauf dieser Arbeit erfolgte meinerseits die Aufklärung der Genfunktion durch heterologe Expression in E. coli und die anschließende Strukturaufklärung der Enzymprodukte mit Hilfe von Massenspektrometrie (MS) und Kernresonanzspektroskopie (NMR). 5-DMATS katalysiert eine regiospezifische Prenylierung von Indolderivaten an Position C-5. Aufgrund der enormen Bedeutung der Prenylierung an der Strukturvielfalt und damit der biologischen Aktivität, wurden CdpC3PT, BrePT, 5-DMATS und andere bekannte Prenyltransferasen der DMATS-Superfamile zur chemoenzymatischen Synthese von prenylierten Substanzen verwendet. Durch Einsatz von AnaPT, CdpC3PT und CdpNPT, konnten jeweils acht und sechs Stereoisomere von cis-konfigurierten prenylierten Pyrroloindolin-Diketopiperazinen von cyclo-Trp-Ala und cyclo-Trp-Pro Isomeren produziert werden. Die Stereospezifität von AnaPT und CdpC3PT hängt dabei hauptsächlich von der Konfiguration der Tryptophaneinheit in cyclo-Trp-Ala und cyclo-Trp-Pro Isomeren ab. Im Vergleich dazu, zeigte CdpNPT eine geringere Stereoselektivität, aber eine höhere Umsetzungsrate gegenüber den getesteten Substraten. Weiterführend wurden 5-DMATS und FgaPT2 für die chemoenzymatische Synthese von prenylierten Indolcarbazolen eingesetzt. Die Rekonstruktion der Enzymaktivität von 5-DMATS und FgaPT2 in vitro zeigte, dass sie in der Lage sind, die regiospezifische Prenylierung von Indolcarbazolen an der para-Position des N-Atoms zu katalysieren. Dies ist der erste Bericht über derartige prenylierte Indolcarbazole. Desweiteren konnte auch die Akzeptanz einiger Hydroxynaphthalene und Flavonoide durch Indolprenyltransferasen der DMATS Superfamilie nachgewiesen werden, wobei diese eigentlich Substrate der Enzyme der CloQ/NphB-Gruppe, oder der UbiA-Superfamilie darstellen. Neun prenylierte Flavonoide und zwanzig prenylierte Hydroxynaphthalene wurden isoliert und deren Strukturen anschließend durch MS- und NMR-Analysen aufgeklärt. Dabei konnte festgestellt werden, dass für ein akzeptiertes Hydroxynaphthalen, unterschiedliche Enzyme das gleiche prenylierte Hauptprodukt produzieren, natürlich mit einer regulären C-Prenylierung an para- oder ortho-Position zu einer Hydroxygruppe. Bei Flavonoiden, welche von 7-DMATS akzeptiert wurden, war Position C-6 zwischen zwei Hydroxygruppen die bevorzugte Prenylierungsstelle. Die erhaltenen Michaelis-Menten Konstanten (KM) und die Wechselzahlen (kcat) einiger Prenyltransferasen für ausgewählte Hydroxynaphthalene waren vergleichbar mit denen von Indolderivaten. Ergänzend zu Prenyltransferasen wurden noch weitere Gene aus einem putativen Biosynthesecluster für ein prenyliertes Indolalkaloid, das Hexadehydroastechrom (HAS) untersucht. Ein putatives O-Methyltransferasegen hasC und ein putatives Cytochrome P450-Gen hasH, welche in dessen Biosynthese in Aspergillus fumigatus (A. fumigatus) involviert sind. Sie wurden jeweils in die Expressionsvektoren pQE60 und pESC-URA kloniert. Das lösliche His6-HasC wurde erfolgreich in E.coli SG13009 überexprimiert und über Ni-NTA aufgereinigt. Konstrukte für die Co-Expression mit dem Reduktasegen NFIA_083630 aus N. fischeri in pESC-URA und für die Expression als His6-getaggtes Protein in pESC-URA wurden auch für das putative Cytochrome P450-Gen hasH angefertigt.

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