Recently, researchers set out to understand the biosynthetic origins of palmerolide A, a compound known to have specific activity against melanoma. They found their answers in Synoicum adareanum, a sea-squirt.
Across the world’s oceans, marine invertebrates harbour a rich source of natural products that serve both metabolic and ecological roles. For example, sponges, corals and ascidians host a wealth of diverse microbes, some of which have been found to provide a multitude of medicinal and biotechnological applications to science and health. Many of these host-microbe associations are symbiotic, providing metabolic requirements and enabling the production of adaptive features, such as bioluminescence and photoreceptive pigments.
Antarctic marine ecosystems harbour particularly species-rich invertebrate communities, which is why they have been the subject of several investigations over the years. In fact, over the past 30 years, research in the Antarctic has resulted in the identification of over 600 metabolites.
Ascidians, also known as sea-squirts, are marine invertebrates characterised by their rapid development, compact genomes and ease of transgenesis. They are known to be rich sources of bioactive natural products and have been found to harbour polyketide, terpenoid, peptide and alkaloid, some of which have cytotoxic or antimicrobial activities.
Patrick Chain, Senior Scientist and Laboratory Fellow at Los Alamos National Laboratory (LANL), said:
“Throughout the course of disentangling the many genomic fragments of the various species in the microbiome, we discovered that this novel microbe’s genome appears to harbour multiple copies of the genes responsible for palmerolide production. However, the role of each copy and regulation, for example, are unknown. This suggests palmerolide is likely quite important to the bacterium or the host, though we have yet to understand it’s biological or ecological role within this Antarctic setting.”
Further investigating palmerolide A
Recently, a research team from the Desert Research Institute (DRI), LANL and the University of South Florida set out to understand the biosynthetic origins of palmerolide A. This bioactive macrolide, which is thought to be microbially mediated, is known to have specific activity against melanoma and is recognised to hold considerable promise as an anti-cancer therapeutic. Evidence for this was found when tested in the National Cancer Institute 60-cell-line panel. This was hugely exciting as there are currently only a few natural product therapeutics for melanoma. It is thought that palmerolide A has these anti-cancer properties due to its ability to inhibit vacuolar ATPases, which are highly expressed in metastatic melanoma.
In the current study, the scientists investigated the microbiome of Synoicum adareanum using a high-throughput sequencing and bioinformatic strategy. They found that the metagenome-encoded biosynthetic machinery that produces palmerolide A was associated with the genome of Synoicum adareanum. For example, they identified a biosynthetic gene cluster that harbours key features necessary for palmerolide A biosynthesis. Moreover, surveys of ascidian microbiome samples targeting this candidate biosynthetic gene cluster revealed a high correlation between palmerolide gene targets and a single 16S rRNA gene variant.
Importance of Synoicum adareanum
Overall, palmerolide A has the potential to be a chemotherapeutic agent to target melanoma. Therefore, knowing how palmerolide is produced will enable its cultivation, and in time, could eventually provide enough of the compound needed to study its pharmacological properties.
Alison Murray, Research Professor of Biology at the DRI, explained:
“We have long suspected that palmerolide A was produced by one of the many types of bacteria that live within this ascidian host species, S. adareanum. Now, we have actually been able to identify the specific microbe that produces this compound, which is a huge step forward towards developing a naturally-derived treatment for melanoma. This is the first time that we’ve matched an Antarctic natural product to the genetic machinery that is responsible for its biosynthesis. As an anti-cancer therapeutic, we can’t just go to Antarctica and harvest these sea squirts en masse, but now that we understand the underlying genetic machinery, it opens the door for us to find a biotechnological solution to produce this compound.”
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