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Biosynthesis

Leading the way to RiPPs

Nature Chemical Biology volume 11, pages 551–552 (2015)Cite this article

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Many peptide-based natural products require a leader peptide to reach their final modified form, but the identification of general rules for leader peptide interactions have been stymied by the diversity of these molecules. Two papers reporting crystallographic and bioinformatic analysis of these systems now reveal a structurally conserved domain that mediates leader peptide binding.

All RiPPs start out as linear chains of amino acids, referred to as precursor peptides. This is in contrast to natural products made by polyketide synthases (PKS) or nonribosomal peptide synthetases (NRPS), which are assembled one monomer at a time. The RiPP precursor peptide can be further broken down into the leader peptide, which is eventually cleaved off, and the core peptide, which becomes the natural product through the action of one or more maturation enzymes. Although it has been assumed that the leader peptide is a substrate-recognition element that directs the maturation of RiPPs in some way, only recently have crystal structures emerged that show the interaction of a RiPP precursor peptide with a maturation enzyme. The structure of the microcin C7 biosynthetic enzyme MccB bound to its precursor peptide substrate MccA has been determined2. More recently, a structure of the nisin precursor NisA leader peptide in complex with the lanthipeptide biosynthetic enzyme NisB was reported8. These structures provided the first glimpses of leader peptide interactions with maturation enzymes.

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Figure 1: Binding of diverse RiPP precursor peptides to their biosynthetic enzymes is mediated by a conserved domain related to the protein PqqD.

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References

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  1. A. James Link is in the Departments of Chemical and Biological Engineering and Molecular Biology, Princeton University, Princeton, New Jersey, USA.,

    A James Link

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Correspondence to A James Link.

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Link, A. Leading the way to RiPPs. Nat Chem Biol 11, 551–552 (2015). https://doi.org/10.1038/nchembio.1862

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