The C‐Terminal Extended Serine Residue Is Absolutely Required in Nosiheptide Maturation

Liu, Weiying; Ma, Min; Xue, Yanjiu; Liu, Nan; Wang, Shuzhen; Chen, Yijun

doi:10.1002/cbic.201200681

Cited by 23 publications

(17 citation statements)

References 19 publications

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“…; Liu et al . ). Flavohaemoglobins, possess an N‐terminal globin domain (a three‐on‐three a‐helical fold) linked to a C‐terminal domain containing NAD(P)H‐binding and FAD‐binding sites (Vasudevan et al .…”

Section: Resultsmentioning

confidence: 97%

Enhancing nosiheptide production inStreptomyces actuosusby heterologous expression of haemoprotein fromSinorhizobium meliloti

Zhang

Liu

et al. 2016

Lett Appl Microbiol

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Section: Resultsmentioning

confidence: 97%

Enhancing nosiheptide production inStreptomyces actuosusby heterologous expression of haemoprotein fromSinorhizobium meliloti

Zhang

Liu

et al. 2016

Lett Appl Microbiol

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“…One mutagenesis study has shown that substitution of Ser13 does not particularly affect the biosynthetic pathway except for preventing de-acylation to the C-terminal amide by NosA. 331 There has been more interest in optimizing nosiheptide production 332–335 due to its use as a livestock growth promoter. 66, 67 …”

Section: Thiopeptidesmentioning

confidence: 99%

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

et al. 2017

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With advances in sequencing technology, uncharacterized proteins and domains of unknown function (DUFs) are rapidly accumulating in sequence databases and offer an opportunity to discover new protein chemistry and reaction mechanisms. The focus of this review, the formerly enigmatic YcaO superfamily (DUF181), has been found to catalyze a unique phosphorylation of a ribosomal peptide backbone amide upon attack by different nucleophiles. Established nucleophiles are the side chains of Cys, Ser, and Thr which gives rise to azoline/azole biosynthesis in ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products. However, much remains unknown about the potential for YcaO proteins to collaborate with other nucleophiles. Recent work suggests potential in forming thioamides, macroamidines, and possibly additional post-translational modifications. This review covers all knowledge through mid-2016 regarding the biosynthetic gene clusters (BGCs), natural products, functions, mechanisms, and applications of YcaO proteins and outlines likely future research directions for this protein superfamily.

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“…The biosynthetic gene cluster of nosiheptide was elucidated in 2009 (21). Several groups have focused on the biosynthesis of nosiheptide, and progress has subsequently been made (26)(27)(28)(29)(30)(31)(32)(33). However, these studies have been limited to only the late modification stage without the involvement of the leader peptide.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, understanding the functions or roles of the leader peptide could certainly provide an insightful basis to reveal all of the biosynthetic steps in nosiheptide biosynthesis. In addition, based on the feasibility of genetic manipulation in S. actuosus ATCC 25421, exploration of the roles of the leader peptide in the biosynthetic gene cluster of nosiheptide has become approachable (21,27,28).…”

Section: Discussionmentioning

confidence: 99%

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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The C‐Terminal Extended Serine Residue Is Absolutely Required in Nosiheptide Maturation

Abstract: Serine qua non: Substitution of the extended Ser13 in the core peptide of nosiheptide by analogous amino acids prevented enamide dealkylation of the terminal residue for nosiheptide maturation.

Cited by 23 publications

References 19 publications

Enhancing nosiheptide production inStreptomyces actuosusby heterologous expression of haemoprotein fromSinorhizobium meliloti

Enhancing nosiheptide production inStreptomyces actuosusby heterologous expression of haemoprotein fromSinorhizobium meliloti

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

Mutagenesis of NosM Leader Peptide Reveals Important Elements in Nosiheptide Biosynthesis

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