Characterization of an Environmental DNA-Derived Gene Cluster that Encodes the Bisindolylmaleimide Methylarcyriarubin

Bisindolylmaleimides represent a naturally occurring class of metabolites that are of interest because of their protein kinase inhibition activity. From a metagenomic library constructed with soil DNA, we identified the four gene mar cluster, a bisindolylmaleimide gene cluster that encodes for methy...

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Bibliographic Details
Published in:Chembiochem : a European journal of chemical biology 2014-04, Vol.15 (6), p.815-821
Main Authors: Chang, Fang-Yuan, Brady, Sean F.
Format: Article
Language:English
Subjects:
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Bacteriology
biosynthesis
bisindolylmaleimides
Cloning, Molecular
Deoxyribonucleic acid
DNA
DNA - metabolism
Escherichia coli
Escherichia coli - metabolism
Gene Library
Genes
Indoles - chemistry
Indoles - metabolism
Kinases
Maleimides - chemistry
Maleimides - metabolism
Metagenomics
Multigene Family
natural products
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Rieske dioxygenase
Soil Microbiology
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Summary:Bisindolylmaleimides represent a naturally occurring class of metabolites that are of interest because of their protein kinase inhibition activity. From a metagenomic library constructed with soil DNA, we identified the four gene mar cluster, a bisindolylmaleimide gene cluster that encodes for methylarcyriarubin (1) production. Heterologous expression of the mar gene cluster in E. coli revealed that the Rieske dioxygenase MarC facilitates the oxidative decarboxylation of a chromopyrrolic acid (CPA) intermediate to yield the bisindolylmaleimide core. The characterization of the mar cluster defines a new role for CPA in the biosynthesis of structurally diverse bacterial tryptophan dimers. Gene cluster at work: The biosynthetic gene cluster for the bisindolylmaleimide tryptophan dimer methylarcyriarubin was discovered from a soil metagenomic library and heterologously expressed in E. coli. The Rieske dioxygenase MarC generates the bisindolylmaleimide core by facilitating oxidative decarboxylation of a chromopyrrolic acid intermediate.
ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201300756