Guanitrypmycin Biosynthetic Pathways Imply Cytochrome P450 Mediated Regio- and Stereospecific Guaninyl-Transfer Reactions.
Angew Chem Int Ed Engl
; 58(33): 11534-11540, 2019 08 12.
Article
en En
| MEDLINE
| ID: mdl-31206992
ABSTRACT
Mining microbial genomes including those of Streptomyces reveals the presence of a large number of biosynthetic gene clusters. Unraveling this genetic potential has proved to be a useful approach for novel compound discovery. Here, we report the heterologous expression of two similar P450-associated cyclodipeptide synthase-containing gene clusters in Streptomyces coelicolor and identification of eight rare and novel natural products, the C3-guaninyl indole alkaloids guanitrypmycins. Expression of different gene combinations proved that the cyclodipeptide synthases assemble cyclo-l-Trp-l-Phe and cyclo-l-Trp-l-Tyr, which are consecutively and regiospecifically modified by cyclodipeptide oxidases, cytochrome P450 enzymes, and N-methyltransferases. In vivo and in vitro results proved that the P450 enzymes function as key biocatalysts and catalyze the regio- and stereospecific 3α-guaninylation at the indole ring of the tryptophanyl moiety. Isotope-exchange experiments provided evidence for the non-enzymatic epimerization of the biosynthetic pathway products via keto-enol tautomerism. This post-pathway modification during cultivation further increases the structural diversity of guanitrypmycins.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Streptomyces
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Sistema Enzimático del Citocromo P-450
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Vías Biosintéticas
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Guanina
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania