Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining

Skinnider, Michael A.; Johnston, Chad W.; Edgar, Robyn; Dejong, Chris A.; Merwin, Nishanth J.; Rees, Philip N.; Magarvey, Nathan A.

doi:10.1073/pnas.1609014113

Cited by 128 publications

(134 citation statements)

References 49 publications

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“…16 The gene cluster is also identified by more recent global surveys of RiPP biosynthetic gene clusters. 17–18 Because the lasso peptide is derived from A. benevestitus , we have named it benenodin-1. Like all other characterized alpha-proteobacterial lasso peptides, the benenodin-1 gene cluster encodes an isopeptidase which linearizes the threaded lasso peptide substrate.…”

Section: Introductionmentioning

confidence: 99%

Lasso Peptide Benenodin-1 Is a Thermally Actuated [1]Rotaxane Switch

et al. 2017

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Mechanically interlocked molecules that change their conformation in response to stimuli have been developed by synthetic chemists as building blocks for molecular machines. Here we describe a natural product, the lasso peptide benenodin-1, which exhibits conformational switching between two distinct threaded conformers upon actuation by heat. We have determined the structures of both conformers and have characterized the kinetics and energetics of the conformational switch. Single amino acid substitutions to benenodin-1 generate peptides that are biased to a single conformer, showing that the switching behavior is potentially an evolvable trait in these peptides. Lasso peptides such as benenodin-1 can be recognized and cleaved by enzymes called lasso peptide isopeptidases. We show that only the native conformer of benenodin-1 is cleaved by its cognate isopeptidase. Thus thermally-induced conformational switching of benenodin-1 may also be relevant to the biological function of these molecules.

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Section: Introductionmentioning

confidence: 99%

Lasso Peptide Benenodin-1 Is a Thermally Actuated [1]Rotaxane Switch

et al. 2017

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“…Although the vast majority of known lanthipeptides are bactericidal (9,10), some can act as signaling molecules (11,12) or morphogenetic peptides (13). The function of prochlorosins, as well as the products of several other recently discovered lanthipeptide pathways in bacteria (14), remains unknown.…”

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confidence: 99%

Evolutionary radiation of lanthipeptides in marine cyanobacteria

Cubillos-Ruiz

Berta-Thompson

Becker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

114

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Lanthipeptides are ribosomally derived peptide secondary metabolites that undergo extensive posttranslational modification. Prochlorosins are a group of lanthipeptides produced by certain strains of the ubiquitous marine picocyanobacteria Prochlorococcus and Synechococcus. Unlike other lanthipeptide-producing bacteria, picocyanobacteria use an unprecedented mechanism of substrate promiscuity for the production of numerous and diverse lanthipeptides using a single lanthionine synthetase. Through a cross-scale analysis of prochlorosin biosynthesis genes-from genomes to oceanic populations-we show that marine picocyanobacteria have the collective capacity to encode thousands of different cyclic peptides, few of which would display similar ring topologies. To understand how this extensive structural diversity arises, we used deep sequencing of wild populations to reveal genetic variation patterns in prochlorosin genes. We present evidence that structural variability among prochlorosins is the result of a diversifying selection process that favors large, rather than small, sequence changes in the precursor peptide genes. This mode of molecular evolution disregards any conservation of the ancestral structure and enables the emergence of extensively different cyclic peptides through short mutational paths based on indels. Contrary to its fast-evolving peptide substrates, the prochlorosin lanthionine synthetase evolves under a strong purifying selection, indicating that the diversification of prochlorosins is not constrained by commensurate changes in the biosynthetic enzyme. This evolutionary interplay between the prochlorosin peptide substrates and the lanthionine synthetase suggests that structure diversification, rather than structure refinement, is the driving force behind the creation of new prochlorosin structures and represents an intriguing mechanism by which natural product diversity arises.icrobial secondary metabolism produces a wealth of small molecules, referred to as natural products. These metabolites are fundamental for the function of microbial communities because they play diverse roles in mediating both biotic and abiotic interactions (1, 2). Studies on the diversity of secondary metabolite biosynthetic pathways in the human gut (3), soil (4), and marine sediments (5) indicate that the production of structurally diverse natural products is an integral feature of microbial communities. The oligotrophic ocean is the largest ecosystem on Earth, yet little is known about secondary metabolite production in planktonic marine microbial communities in part because their dilute habitat presents an unconventional stage for the action of these types of often-secreted compounds.A survey of secondary metabolite pathways in sequenced genomes of Prochlorococcus and Synechococcus, the most abundant phytoplankton groups in the ocean, revealed the presence of a lanthipeptide biosynthesis pathway (6). The compounds produced by this pathway were named prochlorosins and are the first natural products identified in marine...

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“…2 An area of increasing focus is the application of RiPP enzymes to problems in pharmaceutical discovery and development. One potential application is in improving the pharmacological properties of linear peptide drugs.…”

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confidence: 99%

Enzymatic N- and C-Protection in Cyanobactin RiPP Natural Products

et al. 2017

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Recent innovations in peptide natural product biosynthesis reveal a surprising wealth of previously uncharacterized biochemical reactions that have potential applications in synthetic biology. Among these, the cyanobactins are noteworthy because these peptides are protected at their N- and C-termini by macrocyclization. Here, we use a novel bifunctional enzyme AgeMTPT to protect linear peptides by attaching prenyl and methyl groups at their free N- and C-termini. Using this peptide protectase in combination with other modular biosynthetic enzymes, we describe the total synthesis of the natural product aeruginosamide B and the biosynthesis of linear cyanobactin natural products. Our studies help to define the enzymatic mechanism of macrocyclization, providing evidence against the water exclusion hypothesis of transpeptidation and favoring the kinetic lability hypothesis.

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Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining

Cited by 128 publications

References 49 publications

Lasso Peptide Benenodin-1 Is a Thermally Actuated [1]Rotaxane Switch

Lasso Peptide Benenodin-1 Is a Thermally Actuated [1]Rotaxane Switch

Evolutionary radiation of lanthipeptides in marine cyanobacteria

Enzymatic N- and C-Protection in Cyanobactin RiPP Natural Products

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