Identification of a Tambjamine Gene Cluster in Streptomyces Reveals Convergent Evolution of the Biosynthetic Pathway

Bacterial natural products are an immensely valuable source of therapeutics. As modern DNA sequencing efforts provide increasing numbers of microbial genomes, it is clear that the molecules produced by most natural product biosynthetic gene clusters (BGCs) remain unknown. Genome mining makes use of bioinformatic techniques to elucidate the natural products produced by these “orphan” BGCs. Here, we report the use of sequence similarity networks (SSNs) and genome neighborhood networks (GNNs) to identify an orphan BGC that is responsible for the production of the antitumor tambjamine BE-18591 in Streptomyces albus NRRL B-2362. Although BE-18591 is a close structural analogue of tambjamine YP1 produced by Pseudoalteromonas tunicata, the biosynthetic routes to produce these molecules differ significantly. Notably, the C12-alkylamine tail that is appended onto the bipyrrole core of tambjamine YP1 is derived from fatty acids siphoned from the primary metabolism of the pseudoalteromonad, whilst the S. albus NRRL B-2362 BGC encodes a dedicated system for the de novo biosynthesis of the alkylamine portion of tambjamine BE-18591. These remarkably different biosynthetic strategies represent a striking example of convergent BGC evolution, with selective pressure for the production of tambjamines seemingly leading to the emergence of separate biosynthetic pathways in pseudoalteromonads and streptomycetes that ultimately produce closely related compounds