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Mining genomes to illuminate the specialized chemistry of life

Abstract

All organisms produce specialized organic molecules, ranging from small volatile chemicals to large gene-encoded peptides, that have evolved to provide them with diverse cellular and ecological functions. As natural products, they are broadly applied in medicine, agriculture and nutrition. The rapid accumulation of genomic information has revealed that the metabolic capacity of virtually all organisms is vastly underappreciated. Pioneered mainly in bacteria and fungi, genome mining technologies are accelerating metabolite discovery. Recent efforts are now being expanded to all life forms, including protists, plants and animals, and new integrative omics technologies are enabling the increasingly effective mining of this molecular diversity.

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Fig. 1: Life’s chemical diversity.
Fig. 2: Linking genes to molecules using metabolomics and transcriptomics.
Fig. 3: Function-first genome mining approaches.

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Acknowledgements

This work was supported by the US National Institutes of Health (NIH) (F32-GM129960 to T.dR. and R01-GM085770 to B.S.M.) and European Research Council Starting Grant 948770-DECIPHER (to M.H.M.). The authors thank members of the Moore and Medema laboratories for helpful discussions.

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The authors contributed equally to all aspects of the article.

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Correspondence to Bradley S. Moore.

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M.H.M. is a co-founder of Design Pharmaceuticals and a member of the scientific advisory board of Hexagon Bio. The other authors declare no competing interests.

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Glossary

Natural products

Organic compounds originating from living organisms or natural sources, often prized for their medicinal properties or other biological activities of utility to humanity. The term is typically used to refer to products of secondary metabolism, but also includes primary metabolites.

Specialized metabolites

Natural compounds of limited clade-specific or niche-specific distribution, known or presumed to have a specialized role in ecology or physiology.

Secondary metabolites

Metabolites that are not strictly required for growth and development, as opposed to primary metabolites, but are often important for survival of an organism in its environment. In the classical meaning, secondary metabolites do not include proteins or large gene-derived peptides that are not post-translationally modified by enzymes.

Siderophore

A metabolite that binds (chelates) iron ions from the environment and is re-imported back into a cell for iron acquisition. Other ‘metallophores’ bind trace metals such as zinc and copper.

Biosynthetic genes

Genes encoding enzymes that catalyse transformations in a biosynthetic pathway.

Ribosomally synthesized and post-translationally modified peptide

(RiPP). A peptide biosynthesized through the action of tailoring enzymes on a ribosomally translated precursor peptide.

Heterologous expression

Expression of one or more genes originating from one organism in another organism; often used to obtain higher production titres or to independently verify their chemical structure or biological function.

Biosynthetic gene clusters

(BGCs). Sets of genes that are physically co-located on a chromosome and together encode the production, regulation and transport of one or more specific metabolites.

Polyketide synthases

Enzymes involved in the biosynthesis of polyketide metabolites; some form modular assembly lines of multidomain proteins, whereas others act as stand-alone enzymes.

Non-ribosomal peptide synthetase

(NRPS). An enzyme involved in the polymerization of amino acids or other organic acids into peptide metabolites without involvement of the ribosome.

Horizontal gene transfer

Acquisition of genetic material by one organism, originating from another. This is often facilitated by plasmids, viruses or mobile elements.

Profile hidden Markov models

(pHMMs). Computational models, trained on a multiple-sequence alignment of a protein family, used to assess whether proteins are part of (or related to) a family.

Gene cluster families

Families comprising a set of similar biosynthetic gene clusters across strains or species, the members of which are responsible for the production of the same or very similar metabolites.

Heterologous host

An organism different from the source organism of a gene under investigation, usually a model organism with a well-developed genetic toolkit. A heterologous host optimized for a specific biotechnological application such as small-molecule production is sometimes called a ‘chassis’.

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Medema, M.H., de Rond, T. & Moore, B.S. Mining genomes to illuminate the specialized chemistry of life. Nat Rev Genet 22, 553–571 (2021). https://doi.org/10.1038/s41576-021-00363-7

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