Ribosomally Synthesized and Post‐Translationally Modified Peptide Natural Products: New Insights into the Role of Leader and Core Peptides during Biosynthesis

Xiao, Yang; Donk, Wilfred A. van der

doi:10.1002/chem.201300401

Cited by 101 publications

(107 citation statements)

References 182 publications

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“…The present study also indicated that most of single-site mutations could be well tolerated during the maturation process, which is in agreement with the findings on other RiPPs showing a largely relaxed substrate specificity for leader peptides (4,8,35,43,44). Additionally, single-site Ala scanning mutagenesis of the N terminus of the leader peptide (excluding D-36A) could increase the production of nosiheptide to various degrees.…”

Section: Discussionsupporting

confidence: 91%

“…Therefore, we focused only on the C-terminal SA motif in this study, and subsequently the SA motif was changed to GG and other sequences that exist in other reported thiopeptides. The variations of nosiheptide production caused by the changes of this region indicated that the sequence of this region is not very restricted, which is different from the case for other leader peptides that are cleaved by proteases with lower tolerance to substitution (8).…”

Section: Discussionmentioning

confidence: 64%

“…For many RiPPs, proteolysis is a common mechanism for the removal of leader peptides in the maturation process (4,8). From the sequence alignments with other thiopeptides, we did not identify any other conserved regions in the C-terminal part of the leader peptide except for an SA motif at the junction between the leader peptide and the core peptide.…”

Section: Discussionmentioning

confidence: 90%

“…Generally, the leader peptide is important for most but not all biosynthetic enzymes and is removed before the maturation of final natural products (8). For many RiPPs, proteolysis is a common mechanism for the removal of leader peptides in the maturation process (4,8).…”

Section: Discussionmentioning

confidence: 99%

“…These features add more diversity of the leader peptides in RiPPs. During the past decade, the roles of leader peptides in the biosynthesis of ribosomal natural products have been explored, suggesting that leader peptides may play one or more functions during the maturation of RiPPs (4,8). However, some proposed functions have not been experimentally confirmed and generally accepted thus far.…”

mentioning

confidence: 99%

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Mutagenesis of NosM Leader Peptide Reveals Important Elements in Nosiheptide Biosynthesis

Jin

Xue

et al. 2017

Appl Environ Microbiol

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Nosiheptide, a typical member of the ribosomally synthesized and posttranslationally modified peptides (RiPPs), exhibits potent activity against multidrugresistant Gram-positive bacterial pathogens. The precursor peptide of nosiheptide (NosM) is comprised of a leader peptide with 37 amino acids and a core peptide containing 13 amino acids. To pinpoint elements in the leader peptide that are essential for nosiheptide biosynthesis, a collection of mutants with unique sequence features, including N-and C-terminal motifs, peptide length, and specific sites in the leader peptide, was generated by mutagenesis in vivo. The effects of various mutants on nosiheptide biosynthesis were evaluated. In addition to the necessity of a conserved motif LEIS box, native length and the N-terminal 12 amino acid residues were indispensable, and single-site substitutions of these 12 amino acid residues resulted in changes ranging from a greater-than-5-fold decrease to a 2-fold increase of nosiheptide production, depending on the sites and substituted residues. Moreover, although the C-terminal motif is not conservative, significant effects of this portion on nosiheptide production were also evident. Taken together, the present results further highlight the importance of the leader peptide in nosiheptide biosynthesis, and provide new insights into the diversity and specificity of leader peptides in the biosynthesis of various RiPPs.IMPORTANCE As a representative thiopeptide, nosiheptide exhibits excellent antibacterial activity. Although the biosynthetic gene cluster and several modification steps have been revealed, the presence and roles of the leader peptide within the precursor peptide of the nosiheptide gene cluster remain elusive. Thus, identification of specific elements in the leader peptide can significantly facilitate the genetic manipulation of the gene cluster for increasing nosiheptide production or generating diverse analogues. Given the complexity of the biosynthetic process, the instability of the leader peptide, and the unavailability of intermediates, cocrystallization of intermediates, leader peptide, and modification enzymes is currently not feasible. Therefore, a mutagenesis approach was used to construct a series of leader peptide mutants to uncover a number of crucial and characteristic elements affecting nosiheptide biosynthesis, which moves a considerable distance toward a thorough understanding of the biosynthetic machinery for thiopeptides.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Mutagenesis of NosM Leader Peptide Reveals Important Elements in Nosiheptide Biosynthesis

Jin

Xue

et al. 2017

Appl Environ Microbiol

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Dual substrate‐controlled kinase activity leads to polyphosphorylated lasso peptides

et al. 2016

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Edited by Alfonso ValenciaLasso peptides are characterized by their peculiar lariat knot-like structure. Except for maturation of this fold, post-translational modifications of lasso peptides are rare. However, we recently delineated the biosynthetic pathway of a post-translationally phosphorylated lasso peptide, paeninodin. In this study, further investigation of two kinases revealed their ability to transfer multiple phosphate groups onto precursor peptide substrates, ultimately leading to polyphosphorylated lasso peptides. We found that this polyphosphorylating activity depended on the identity of the phosphate donor and the sequence of the precursor peptide. Our investigations provide new insight into the remarkable strategies for chemical diversification employed by the lasso peptide biosynthetic machinery.

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Site‐Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands

2019

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Site-selective nitrene transfer to di-and polyene substrates has been achieved using designed peptide-embedded bioxazoline ligands capable of binding copper. In model 1,3-diene substrates, the olefinic position proximal to a directing group was selectively functionalized. Additional studies indicate that this selectivity stems from non-covalent substrate-catalyst interactions. The peptide-mediated nitrene transfer was also applied to polyene natural product retinol and selective proximal functionalization allowed access to a cis-pyrroline modified retinoid.

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Ribosomally Synthesized and Post‐Translationally Modified Peptide Natural Products: New Insights into the Role of Leader and Core Peptides during Biosynthesis

Cited by 101 publications

References 182 publications

Mutagenesis of NosM Leader Peptide Reveals Important Elements in Nosiheptide Biosynthesis

Mutagenesis of NosM Leader Peptide Reveals Important Elements in Nosiheptide Biosynthesis

Dual substrate‐controlled kinase activity leads to polyphosphorylated lasso peptides

Site‐Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands

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