Marine microbiome: a treasure trove for the discovery of enzymes and bioactive molecules

DNA sequencing of the marine microbiome reveals a treasure trove of new enzymes and bioactive molecules. © Helena Klein (illusion), ZHdK.

The ocean is the largest habitat on our planet and covers 71% of its surface. Each drop of water contains thousands of microbial cells, which together form the microbiome of the ocean. This complex ecosystem is the engine of biogeochemical cycles on Earth and the basis of many global food chains. Through several exploration missions, such as expeditions Tara Oceans, we now have access to genetic material from samples collected across the globe. However, more than two-thirds of these DNA sequencing data from marine microbial communities (metagenomers) cannot be linked to genomes from known species. This largely unexplored biodiversity is a likely source of many new biochemical compounds with potential uses in biotechnology and medicine.

Based on the results of Tara Oceans as well as other international projects (Malaspina and Biogeotrace expeditions, Hawaii and Bermuda time series), a team of scientists analyzed the metagenomics of more than 1,000 samples from seawater covering all the oceans.

Using state-of-the-art calculation methods, researchers were able to reconstruct 26,293 microbial genomes and uncover thousands of new species. They integrated these with already published genomes to build the Ocean Microbiomics Database (OMD), which represents 40 to 60% of the metagenomic data collected in the high seas.

Exploration of this genomic resource has revealed more than 40,000 biosynthetic gene clusters (BGCs), groups of genes that encode pathways for the synthesis of biochemical compounds. These BGCs can be grouped into 7,000 families, half of which are expected to be new. In addition to their crucial ecological functions, many of these compounds (also called specialized metabolites) are likely to be important from a biotechnological or medical point of view.

By studying the distribution of these synthetic pathways, the researchers discovered a new line of bacteria with a particularly high number and diversity of BGCs. This bacterial family was therefore named after Eudora, the Nereid (sea nymph) of precious gifts in Greek mythology. To explore its promise, the team has experimentally analyzed two of these BGCs and effectively characterized new biosynthetic enzymes and natural compounds. The first synthetic route, called phospeptin, produces a peptide that inhibits proteases, providing a new chemical framework for potential therapeutic development. The second synthetic route, called pythonamide, produces a new, particularly long and complex peptide as well as a new family of enzymes capable of catalyzing the addition of methyl groups to the backbone of proteins – a very difficult reaction that could be particularly useful in the case of certain biotechnological applications.

This work provides an unprecedented insight into microbes across the world’s oceans and their biosynthetic abilities. This compilation represents an atlas to guide future research, whether in the field of marine ecology, evolution, biotechnology or natural products. By combining computational and molecular methods, the team was able to identify the functions of genetic sequences from microbes belonging to unknown genera and from which no members have been grown so far.

However, the researchers characterized only two synthetic pathways among thousands. A wealth of biochemical compounds and biosynthetic enzymes therefore need to be discovered and OMD is freely available (https://microbiomics.io/ocean/) as a resource for the scientific community. The researchers therefore invite researchers from around the world to join them in their exploration of marine microbial diversity to uncover new enzymes, synthetic pathways and specialized metabolites and to illuminate their ecological functions as well as their potential uses.

This study is also part of the United Nations Decade of Marine Science by examining the potential of the marine microbiome for bioprospecting and demonstrating the need to learn more about it. An article edited by Tara Oceans, was published simultaneously in the journal The microbiology of nature (https://www.nature.com/articles/s41564-022-01145-5) and addresses these issues more generally by outlining priorities for marine microbiome research for the coming years.

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3D illustration of the bioactive phospeptin molecule. © Helena Klein (illusion), ZHdK.

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