Multiple Oxidative Routes towards the Maturation of Nosiheptide

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

doi:10.1002/cbic.201300427

Cited by 36 publications

(51 citation statements)

References 16 publications

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“…Currently, these include thiocillin, 52, 54, 249, 250 thiostrepton, 54, 56, 251 siomycin, 54 nosiheptide, 53, 252, 253 GE2270, 55, 254, 255 thiomuracin, 45, 55 nocathiacin, 256, 257 cyclothiazomycin, 258, 259 TP-1161, 260 GE37468, 261 berninamycin, 262 lactocillin, 263 nocardithiocin, 264 and lactazole. 265 Many natural congeners of these compounds are known to be produced by the same BGC.…”

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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Section: Thiopeptidesmentioning

confidence: 99%

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

et al. 2017

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“…5E ). These observations are supported by the fact that the catalytic power of NosA was completely abolished after removing these two hydroxyl groups in the substrate 17 . Moreover, the –OH group in pyridine ring is obviously more acidic than –OH group next to the carbonyl group in the substrate, which could interpret why the side-chain of residue K49 of NosA easily interacts with the –OH group in pyridine ring.…”

Section: Resultsmentioning

confidence: 65%

“…It was reported that the removal of two –OH groups on the substrate (highlighted in red and in blue in Fig. 1 , respectively) (by knockouting the genes nosC and nosB in nosiheptide biosynthesis responsible for these –OH groups formation, respectively) made NosA completely lose the catalytic activities 17 , suggesting that these two –OH groups in the substrate are important for the catalytic reaction. Interestingly, as shown in supporting information, Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure-based Mechanistic Insights into Terminal Amide Synthase in Nosiheptide-Represented Thiopeptides Biosynthesis

Liu

Guo

Zhang

et al. 2015

Sci Rep

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Nosiheptide is a parent compound of thiopeptide family that exhibit potent activities against various bacterial pathogens. Its C-terminal amide formation is catalyzed by NosA, which is an unusual strategy for maturating certain thiopeptides by processing their precursor peptides featuring a serine extension. We here report the crystal structure of truncated NosA1-111 variant, revealing three key elements, including basic lysine 49 (K49), acidic glutamic acid 101 (E101) and flexible C-terminal loop NosA112-151, are crucial to the catalytic terminal amide formation in nosiheptide biosynthesis. The side-chain of residue K49 and the C-terminal loop fasten the substrate through hydrogen bonds and hydrophobic interactions. The side-chain of residue E101 enhances nucleophilic attack of H2O to the methyl imine intermediate, leading to Cα-N bond cleavage and nosiheptide maturation. The sequence alignment of NosA and its homologs NocA, PbtH, TpdK and BerI, and the enzymatic assay suggest that the mechanistic studies on NosA present an intriguing paradigm about how NosA family members function during thiopeptide biosynthesis.

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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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Multiple Oxidative Routes towards the Maturation of Nosiheptide

Cited by 36 publications

References 16 publications

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

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

Structure-based Mechanistic Insights into Terminal Amide Synthase in Nosiheptide-Represented Thiopeptides Biosynthesis

Mutagenesis of NosM Leader Peptide Reveals Important Elements in Nosiheptide Biosynthesis

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