Publikationsserver der Universitätsbibliothek Marburg

Titel:Molekularbiologische und biochemische Untersuchungen zur Biosynthese von Ergotalkaloiden in Pilzen der Familien Trichocomaceae und Arthrodermataceae
Autor:Wallwey, Christiane
Weitere Beteiligte: Li, Shu-Ming (Prof. Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0490
DOI: https://doi.org/10.17192/z2012.0490
URN: urn:nbn:de:hebis:04-z2012-04906
DDC: Naturwissenschaften
Titel(trans.):Molecular biological and biochemical investigations on the biosynthesis of ergot alkaloids in fungi of the families Trichocomaceae and Arthrodermataceae
Publikationsdatum:2012-07-11
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Aspergillus fumigatus, Arthrodermataceae, Biosynthese, Arthroderma benhamiae, Dissertation, Schlauchpilze, Arthroderma benhamiae, Arthrodermataceae, Ergotalkaloide, Gencluster

Zusammenfassung:
Ergotalkaloide (EA) sind eine komplexe Familie von Indolderivaten mit einem tetrazyklischen Ergolinringsystem, die von Pilzen aus zwei unterschiedlichen Familien produziert werden. Dies sind z.B. Aspergillus fumigatus (A. fumigatus) aus der Familie Trichocomaceae oder Claviceps purpurea (C. purpurea) aus der Familie Clavicipitaceae. EA besitzen unterschiedliche Strukturen und dadurch auch unterschiedliche biologische Aktivitäten. Aufgrund ihrer Strukturen können EA in drei Gruppen eingeteilt werden: Alkaloide vom Clavin-Typ, Ergoamide und Ergopeptine. Ergoamide sind Amid-Derivate der D-Lysergsäure, während Ergopeptine Peptid-Derivate der D-Lysergsäure darstellen. Alkaloide vom Clavin-Typ enthalten zwar das tetrazyklische Ergolinringsystem, sind jedoch keine Derivate der D-Lysergsäure. Ein Beispiel für diese Gruppe ist Fumigaclavin C, das Endprodukt der Ergotalkaloidbiosynthese in A. fumigatus. Die Pilze der Familie Trichocomaceae produzieren nur Alkaloide vom Clavin-Typ, während Pilze der Familie Clavicipitaceae hauptsächlich Ergoamide und Ergopeptine bilden. Durch den Vergleich der Gencluster für die Biosynthese von EA verschiedener Produzenten konnten sieben homologe Gene identifiziert werden. Es wurde die Hypothese aufgestellt, dass diese Gene in die Bildung des tetrazyklischen Ergolinringsystems involviert sein müssen. In früheren Studien konnten zwei der sieben homologen Gene, fgaPT2 und fgaMT aus A. fumigatus, den entsprechenden Schritten in der Biosynthese des Ergolinrings zugeordnet werden. Die Prenyltransferase FgaPT2 katalysiert den ersten Schritt, die Prenylierung von L-Tryptophan. Das Produkt 4-Dimethylallyltryptophan wird im nächsten Schritt durch die N-Methyltransferase FgaMT zu N-Methyl-4-Dimethylallyltryptophan umgesetzt. Im Rahmen der vorliegenden Dissertation konnten die Funktionen von drei weiteren der sieben homologen Gene aus A. fumigatus, fgaDH, fgaOx3 und fgaFS, in der Biosynthese von Fumigaclavin C aufgeklärt werden. FgaDH besitzt die konservierten Motive von klassischen Short-Chain Dehydrogenasen/Reduktasen (SDRs), weist aber ansonsten keine Sequenzähnlichkeiten zu SDRs oder anderen bekannten Proteinen auf. Es konnte gezeigt werden, dass FgaDH die Oxidation von Chanoclavin-I zu Chanoclavin-I-Aldehyd katalysiert, wobei NAD+ als Kofaktor benötigt wird. Die Struktur von Chanoclavin-I-Aldehyd konnte eindeutig durch NMR- und MS-Analysen nachgewiesen werden. Die KM-Werte für Chanoclavin-I und NAD+ betrugen 0,27 bzw. 1,1 mM. Eine Wechselzahl von 0,38 s-1 wurde aus den kinetischen Parametern berechnet. Das Protein FgaOx3 enthält eine old yellow enzyme-like FMN binding domain, während FgaFS keine konservierten Bereiche oder sonstige Ähnlichkeiten zu bekannten Proteinen aufweist. Die beiden Proteine FgaOx3 und FgaFS sind zusammen für die Umsetzung von Chanoclavin-I-Aldehyd zu Festuclavin verantwortlich. In Abwesenheit von FgaFS kommt es durch FgaOx3 unter Einbau von Sauerstoff zur Bildung eines Produktgemischs, das aus zwei Stereoisomeren besteht und durch FgaFS nicht weiter umgesetzt wird. Die Strukturen von Festuclavin und den zwei Stereoisomeren konnten durch detailierte NMR- und MS-Analysen aufgeklärt werden. Anhand der gesammelten Daten wurde ein Reaktionsmechanismus ausgehend von Chanoclavin-I-Aldehyd postuliert. Desweiteren konnte in dieser Dissertation durch eine Analyse der Genomsequenzen verschiedener Pilze ein putatives Ergotalkaloidgencluster in den Pilzen der Familie Arthrodermataceae identifiziert werden. Das Cluster besteht aus fünf Genen, deren Homologe in A. fumigatus und C. purpurea in die Bildung von Chanoclavin-I-Aldehyd aus L-Tryptophan involviert sind. Es konnten keine homologen Gene zu denen gefunden werden, die für die weitere Umsetzung von Chanoclavin-I-Aldehyd zu Festuclavin bzw. Agroclavin oder für die späteren Schritte im Biosyntheseweg von A. fumigatus bzw. C. purpurea verantwortlich sind. Aus dem putativen Gencluster von Arthroderma benhamiae (A. benhamiae) wurde das Gen ARB_04646, welches das Homolog zu fgaDH ist, mit korrigierter Intron/Exon-Struktur amplifiziert, kloniert und erfolgreich exprimiert. Das Enzym bekam die Bezeichnung ChaDH. ChaDH katalysiert wie sein Homolog FgaDH in Anwesenheit von NAD+ die Oxidation von Chanoclavin-I. Das enzymatische Produkt konnte durch NMR- und MS-Analysen eindeutig als Chanoclavin-I-Aldehyd identifiziert werden. Die KM-Werte für Chanoclavin-I und NAD+ betrugen 0,09 bzw. 0,36 mM. Aus den kinetischen Parametern wurde eine Wechselzahl von 0,76 s-1 berechnet. In den Kulturüberständen von A. benhamiae konnten keine EA nachgewiesen werden. Die Expressionsanalyse der Gene zeigte, dass unter den gewählten Laborbedingungen keine detektierbare Expression stattfand. In dieser Arbeit konnte somit eine dritte pilzliche Familie identifiziert werden, die zumindest die genetischen Informationen für die Biosynthese von EA bzw. Chanoclavin-I-Aldehyd enthält.

Summary:
Ergot alkaloids are a complex family of indol derivatives with the typical tetracyclic ergoline ringsystem, which are produced by fungi of two different families, e.g. Aspergillus fumigatus (A. fumigatus), from the family Trichocomaceae, and Claviceps purpurea (C. purpurea), from the family Clavicipitaceae. Ergot alkaloids exhibit different structures and therefore diverse biological activities. Based on the structures ergot alkaloids can be divided into three groups: clavine-type alkaloids, ergoamides and ergopeptines. Ergoamides and ergopeptines are amide and peptide derivatives of D-lysergic acid, respectively. Clavin-Type alkaloids consist merely of the ergoline ringsystem and are no D-lysergic acid derivatives. An example for a clavine-type alkaloid is fumigaclavine C, the end product of the ergot alkaloid biosynthetic pathway in A. fumigatus. Fungi of the family Trichocomaceae are producers of clavine-type alkaloids, whereas some members of the family Clavicipitaceae produce mainly ergoamides and ergopeptines. The comparison of the biosynthetic gene clusters of different ergot alkaloid producers led to identification of seven homologous genes. It was speculated that these genes are involved in the formation of the tetracyclic ergoline ring system. In previous studies, two of the seven homologous genes, fgaPT2 and fgaMT of A. fumigatus, were assigned to the corresponding step in the biosynthesis of the ergoline ring. The gene fgaPT2 encodes a prenyltransferase, which catalyzes the first step in the biosynthesis, i.e. prenylation of L-tryptophan. The product 4-dimethylallyltryptophan (4-DMAT) of this reaction is then methylated by N-methyltransferase FgaMT, resulting in the formation of N-methyl-4-dimethylallyltryptophan (4-DMA-L-abrine). In this thesis, functions of three additional genes, fgaDH, fgaOx3 and fgaFS of A. fumigatus, were proven biochemically. FgaDH contains the conserved motifs of classical short-chain dehydrogenases (SDRs), but shows otherwise no significant sequence similarity to SDRs or other known proteins. It was shown that FgaDH catalyses the oxidation of chanoclavine-I to chanoclavine-I aldehyde in the presence of NAD+. The structure of chanoclavine-I aldehyde was unequivocally elucidated by NMR and MS analysis. The KM value was determined as 0.27 mM for chanoclavine-I and 1.1 mM for NAD+, respectively The turnover number was determined as 0.38 s-1. The protein FgaOx3 contains an old yellow enzyme-like FMN binding domain, whereas FgaFS has no conserved regions or similarity to known proteins. FgaOx3 and FgaFS together are responsible for the formation of festuclavine from chanoclavine-I aldehyde. In the abscence of FgaFS a mixture of two stereoisomers is generated by FgaOx3 under consumption of oxygen. The isomers could not be further converted by FgaFS. The structures of these two stereoisomers as well as that of festuclavine were unequivocally elucidated by 1D- and 2D-NMR and MS analysis. On the basis of the obtained data, a reaction mechanism with chanoclavine-I aldehyde as substrate was postulated. Furthermore, a putative ergot alkaloid gene cluster was identified in fungi of the family Arthrodermataceae by analysis of genome sequences. The cluster contains five genes whose enzymes have homology to the enzymes, which are involved in the formation of chanoclavine-I aldehyde from L-tryptophan in A. fumigatus und C. purpurea. Homologues neither to the genes responsible for the conversion of chanoclavine-I aldehyde to festuclavine or agroclavine nor to the genes involved in the later steps of ergot alkaloid biosyntheses in A. fumigatus and C. purpurea exist in the genomes of these fungi. The fgaDH homologue from the putative ergot alkaloid cluster, ARB_04646, was amplified from gDNA of Arthroderma benhamiae (A. benhamiae), cloned and expressed in E. coli. The enzyme named ChaDH catalyses also the oxidation of chanoclavine-I in presence of NAD+. The enzymatic product was identified as chanoclavine-I aldehyde by NMR and MS analysis. The KM values were determined as 0.09 mM for chanoclavine-I and 0.36 mM for NAD+, respectively. The turnover number was found to be 0.76 s-1. Thus a third fungal family was identified in this thesis, which has at least the genetic information for the biosyntheses of ergot alkaloids or their precursors, i.e. chanoclavine-I aldehyde. But no ergot alkaloids were detectable in the supernatant of A. benhamiae cultures and the analysis of the expression of the five cluster genes by Northern blot showed no detectable expression under the used conditions.

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