Nature's Combinatorial Biosynthesis Produces Vatiamides A-F

Area of Science:

• Biochemistry
• Natural Product Chemistry
• Microbiology

Background:

• Hybrid type I polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) pathways usually follow a linear gene-to-product sequence.
• Understanding microbial biosynthetic pathways is key to discovering novel compounds.

Purpose of the Study:

• To discover and characterize new lipopeptides from the cyanobacterium Moorea producens.
• To investigate the unique biosynthetic pathway of these novel compounds.

Main Methods:

• Genome mining of Moorea producens.
• Application of a fluorogenic azide-based click probe for compound discovery.
• Structural elucidation of isolated compounds.

Main Results:

• Discovery and characterization of vatiamides A-F, structurally diverse alkynylated lipopeptides and their brominated analogues.
• Identification of a unique non-collinear PKS/NRPS system encoded by a 90 kb gene cluster.
• Demonstration of promiscuous PKS-NRPS intermodule docking motifs facilitating combinatorial biosynthesis.

Conclusions:

• The non-collinear PKS/NRPS system in Moorea producens enables the generation of significant molecular diversity.
• Promiscuous docking motifs are crucial for the combinatorial capacity of this unique biosynthetic system.
• This discovery expands the known mechanisms of hybrid PKS/NRPS pathway operation.