Abstract
Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic enzymes that construct core scaffolds or perform peripheral modifications, and can thus define natural product families, introduce pharmacophores and permit metabolic diversification. Modern genomics approaches have greatly enhanced our ability to access and characterize natural product pathways via sequence-similarity-based bioinformatics discovery strategies. However, many biosynthetic enzymes catalyse exceptional, unprecedented transformations that continue to defy functional prediction and remain hidden from us in bacterial (meta)genomic sequence data. In this Review, we highlight exciting examples of unusual enzymology that have been uncovered recently in the context of natural product biosynthesis. These suggest that much of the natural product diversity, including entire substance classes, awaits discovery. New approaches to lift the veil on the cryptic chemistries of the natural product universe are also discussed.
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Acknowledgements
T.A.S. is financially supported by a European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF 344-2018). The authors are additionally grateful for funding from the European Research Council (ERC; ERC Advanced Project SynPlex), the Swiss National Science Foundation (SNF; 31003A_146992/1 and NRP 72 ‘Antimicrobial resistance’, 407240_167051), the Helmut Horten Foundation and the Promedica Foundation. The authors would also like to thank S. Leopold-Messer for comments on the figures.
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T.A.S. researched the literature and wrote the article, in addition to producing all of the figures. J.P. contributed to discussion, writing and reviewing/editing of the manuscript before submission.
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Glossary
- Orphan
-
Biosynthetic genes that can be detected bioinformatically in a natural product biosynthetic gene cluster context but are functionally unassigned or have been assigned an incorrect or nonspecific function.
- Cryptic
-
Functionally unassigned genes not previously recognized as belonging to natural product biosynthesis.
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Scott, T.A., Piel, J. The hidden enzymology of bacterial natural product biosynthesis. Nat Rev Chem 3, 404–425 (2019). https://doi.org/10.1038/s41570-019-0107-1
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DOI: https://doi.org/10.1038/s41570-019-0107-1
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