Discovery
and Synthetic Refactoring of Tryptophan
Dimer Gene Clusters from the Environment
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Abstract
Here we investigate bacterial tryptophan
dimer (TD) biosynthesis
by probing environmental DNA (eDNA) libraries for chromopyrrolic acid
(CPA) synthase genes. Functional and bioinformatics analyses of TD
clusters indicate that CPA synthase gene sequences diverge in concert
with the functional output of their respective clusters, making this
gene a powerful tool for guiding the discovery of novel TDs from the
environment. Twelve unprecedented TD biosynthetic gene clusters that
can be arranged into five groups (A–E) based on their ability
to generate distinct TD core substructures were recovered from eDNA
libraries. Four of these groups contain clusters from both cultured
and culture independent studies, while the remaining group consists
entirely of eDNA-derived clusters. The complete synthetic refactoring
of a representative gene cluster from the latter eDNA specific group
led to the characterization of the erdasporines, cytotoxins with a
novel carboxy-indolocarbazole TD substructure. Analysis of CPA synthase
genes in crude eDNA suggests the presence of additional TD gene clusters
in soil environments