Discovery of a Tambjamine Gene Cluster in Streptomyces Suggests Convergent Evolution in Bipyrrole Natural Product Biosynthesis

Abstract

While bacterial natural products are a valuable source of therapeutics, the molecules produced by most biosynthetic gene clusters remain unknown. Tambjamine YP1, produced by Pseudoalteromonas tunicata, is partially derived from fatty acids siphoned from primary metabolism. A structurally similar tambjamine produced by Streptomyces, BE-18591, had not been linked to a gene cluster. Using enzymes putatively implicated in the construction of these two tambjamines, we used sequence similarity networks and gene knockout experiments to identify the biosynthetic gene cluster responsible for the production of tambjamine BE-18591 in Streptomyces albus. Despite the structural similarities between YP1 and BE-18591, the biosynthesis of the alkylamine tails of these molecules differs significantly, with the S. albus gene cluster putatively encoding a dedicated system for the construction of the fatty acid precursor to BE-18591. These different pathways in Pseudoalteromonas and Streptomyces suggest that evolutionary convergence is operative, with similar selective pressures leading to the emergence of structurally similar tambjamine natural products using different biosynthetic logic.

On the evolution of natural product biosynthesis

“…This is probably best studied within the antimicrobial NPs with new examples being increasingly discovered. Convergent evolution can be via evolutionary convergence of pathways to deliver the same molecule (Fischbach, 2009;Grenade et al, 2021; e.g beta-lactams (Liras and Martín, 2006), fosfomycin in Pseudomonas and Streptomyces (Kim et al, 2012), gerumycin and dentigerumycin (Sit et al, 2015), tambjamines in Pseudoalteromonas and Streptomyces (Grenade et al, 2023) or to deliver highly similar molecules that have converged on the same cellular targets (Fischbach, 2009) (e.g. five structural classes of antibiotic targeting the bacterial ribosome (Hansen et al, 2003), Lipid II (Breukink and Kruijff, 2006), and bacterial cell wall synthesis (Sarkar et al, 2017)).…”

New prodigiosin derivatives – chemoenzymatic synthesis and physiological evaluation against cisplatin-resistant cancer cells

“…1, bottom). [38][39][40][41][42] Despite the structural diversity of prodiginine-related natural products, their biosynthesis resorts to clustered genes, encoding for non-ribosomal peptide synthetases (NRPS) of type II. 36,43 Using the synthesis of prodigiosin (1) as representative example, the assembly employs a convergent route with two key precursors, namely the bipyrrole part (4-methoxy-2,2′-bipyrrole-5-carbaldehyde, MBC 3a) and the monopyrrole part (2-methyl-3-amylpyrrole, MAP 4a), which are consolidated in an ATP-catalysed condensation reaction to give the conjugated tripyrrole scaffold of prodigiosin (1) (Fig.…”

Anti-Malassezia Drug Candidates Based on Virulence Factors of Malassezia-Associated Diseases

“…The diversity of this nitrogen-substituent led to a large variety of derivatives and biological applications. From 2010, Tambjamine derivatives were reported with potent antimicrobial, anticancer, and antimalarial bioactivities [104][105][106][107][108][109][110][111][112]. In 2010, Banwell, Pessoa et al reported the first anti-Malassezia potential of some synthetically derived tambjamines [113].…”