Abstract
Polyketides are a complex family of natural products that often serve competitive or pro-survival purposes but can also demonstrate bioactivity in human diseases as, for example cholesterol lowering agents, anti-infectives, or anti-tumor agents. Marine invertebrates and microbes are a rich source of polyketides. Palmerolide A, a polyketide isolated from the Antarctic ascidian Synoicum adareanum, is a vacuolar-ATPase inhibitor with potent bioactivity against melanoma cell lines. The biosynthetic gene clusters (BGC) responsible for production of secondary metabolites are encoded in the genomes of the producers as discrete genomic elements. A putative palmerolide BGC was identified from a S. adareanum metagenome based on a high degree of congruence with a chemical structure-based retrobiosynthetic prediction. Protein family homology analysis, conserved domain searches, and active site and motif identification were used to confirm the identity and propose the function of the 75 kb trans-acyltransferase (AT) polyketide synthase-non-ribosomal synthase (PKS-NRPS) domains responsible for the synthesis of palmerolide A. Though PKS systems often act in a predictable co-linear sequence, this BGC includes multiple trans-acting enzymatic domains, a non-canonical condensation termination domain, a bacterial luciferase-like monooxygenase (LLM), and multiple copies found within the metagenome-assembled genome (MAG) of Candidatus Synoicohabitans palmerolidicus. Detailed inspection of the five highly similar pal BGC copies suggests the potential for biosynthesis of other members of the palmerolide chemical family. This is the first delineation of a biosynthetic gene cluster from an Antarctic species. These findings have relevance for fundamental knowledge of PKS combinatorial biosynthesis and could enhance drug development efforts of palmerolide A through heterologous gene expression.
Significance Statement Complex interactions exist between microbiomes and their hosts. Increasingly, defensive metabolites that have been attributed to host biosynthetic capability are now being recognized as products of associated microbes. These unique metabolites often have bioactivity in targets of human disease and can be purposed as pharmaceuticals. The molecular machinery for production of palmerolide A, a macrolide that is potent and selective against melanoma, was discovered as a genomic cluster in the microbiome of an Antarctic ascidian. Multiple non-identical copies of this genomic information provide clues to differences in specific enzymatic domains and point to Nature’s ability to perform combinatorial biosynthesis in situ. Harnessing this genetic information may pave a path for development of a palmerolide-based drug.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Classification: Biological sciences, environmental sciences and ecology