Macrolides from Mollusks, Not Microbes?
by Janie
Last year, we covered the microbiological implications of feather pigments in parrots, touching on an unexpected polyketide synthase (PKS) active in an animal rather than a microbe or plant. Now, a redux of animal polyketides! This episode of molecules from unexpected places takes place undersea, starring the clam.
Left: Methyl green-Pyronin staining of the mantle margin confirms that numerous RNA molecules (black arrow) are present in the MpES-mRNA positive position. The green box indicates the mantle margin. Right: FISH targeted to MpES mRNA on the mantle margin section. MpES antisense: FISH using the probe with the reverse complementary sequence of MpES mRNA. MpES sense: FISH using the probe with the same sequence of MpES mRNA. White arrows: MpES mRNA. Adapted from source. Frontispiece: Histological staining of erythromycin in the mantle margin section. Black arrows indicate erythromycin-rich structures. Adapted from source.
The spotted hard clam Meretrix petechialis, commercially cultivated along the coasts of East Asia, turns out to be of human interest for more than its tastiness. Yue et al. (2022) spotted within the clam's transcriptome an mRNA encoding an erythronolide synthase, a PKS responsible for producing an intermediate in erythromycin biosynthesis. Upon closer inspection, these transcripts were located only within the clam's mantle, the soft tissue that peeks out between the two shell halves into the surrounding seawater and secretes the shell-making ingredients calcium carbonate and conchiolin. Further cell-level specialization was taking place here: deeper in that mantle, within special mucus-secreting cells, were both the transcripts and erythromycin itself, as evidenced by mass spec, bacteriostatic assays, and FISH experiments. The transcript is clearly an important player, as RNAi targeted to it decreased both its own level and that of erythromycin. Finally, a trail of genetic and phylogenetic breadcrumbs suggested that the erythromycin in the clam is not of bacterial make: primers specific for the 16S ribosomal DNA of Streptomyces species yielded no PCR product, and an analysis of SNPs in the erythronolide synthase gene (MpES) pointed towards an animal origin. The authors' conclusion? Erythromycin – that entire chemical mosaic of a molecule constructed by a Rube-Goldberg-esque lineup of enzyme domains – is produced by the clam. Shell-shocking much?
It's a fascinating paper. Admittedly, I would have been more convinced if they had checked for 16S amplicons from other Streptomyces species and tested the proposed role of MpES in producing erythromycin by expressing the gene in a heterologous host.
The authors claim this biosynthesis of erythromycin to be an example of convergent evolution between bacteria and animals. It's mindboggling to think about the entire biosynthetic pathway manifesting two separate times along the meander of evolution. After their SNP analysis, they rejected the possibility of gene transfer from microbe to host, a phenomenon that is not out of the ordinary. One example: Ixodes scapulares ticks possess a gene for an antibacterial enzyme that likely originated from the Lyme disease-causing Borrelia, co-opted millions of years ago. Their conclusions also discount another strategy found in invertebrates that associate closely with bacteria, the sequestering of microbial natural products. One example: Elysia rufescens sea slugs are loaded up with defensive toxins that they don't produce in-house but rather steal from the algae they eat, which in turn acquire those compounds from their bacterial endosymbionts.
Some fishy business.
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