Abstract
Cyanobacteria produce a wide range of lipopeptides that exhibit potent membrane-disrupting activities. Laxaphycins consist of two families of structurally distinct macrocyclic lipopeptides that act in a synergistic manner to produce antifungal and antiproliferative activities. Laxaphycins are produced by range of cyanobacteria but their biosynthetic origins remain unclear. Here, we identified the biosynthetic pathways responsible for the biosynthesis of the laxaphycins produced by Scytonema hofmannii PCC 7110. We show that these laxaphycins, called scytocyclamides, are produced by this cyanobacterium and are encoded in a single biosynthetic gene cluster with shared polyketide synthase enzymes initiating two distinct non-ribosomal peptide synthetase pathways. The unusual mechanism of shared enzymes synthesizing two distinct types of products may aid future research in identifying and expressing natural product biosynthetic pathways and in expanding the known biosynthetic logic of this important family of natural products.
Highlights
Natural products are small molecules produced by living organisms (Newman and Cragg, 2016)
Many microbial and cyanobacterial natural products are synthesized by polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS) (Kehr et al, 2011; Dittmann et al, 2015)
We show that the two types of scytocyclamides are synthesized by a branched NRPS/PKS biosynthetic pathway
Summary
Natural products are small molecules produced by living organisms (Newman and Cragg, 2016). Laxaphycins are cyanobacterial cyclic lipopeptides that fall in two distinct structural macrocycles consisting of either amino acids (known as A-type laxaphycins) or amino acids (known as B-type laxaphycins) (Frankmölle et al, 1992a; Luo et al, 2015) Both types include β-aminooctanoic acid (Aoa) or β-aminodecanoic acid (Ada) (Table 1). The nomenclature of laxaphycins is complicated due to the two distinct core types addressed as a single family combined with naming new members after the producing organisms and distinguishing variants with lettering complicates (Table 1). We show that the two types of scytocyclamides are synthesized by a branched NRPS/PKS biosynthetic pathway. These pathways encode shared loading PKS enzymes that initiate two distinct NRPS pathways exceptionally to the colinearity rule. We report the synergistic antifungal activity of scytocyclamides and three new laxaphycin variants (scytocyclamides A2, B2, and B3)
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