Understanding the early stages of peptide formation during the biosynthesis of teicoplanin and related glycopeptide antibiotics

  title={Understanding the early stages of peptide formation during the biosynthesis of teicoplanin and related glycopeptide antibiotics},
  author={Milda Kaniusaite and Julien Tailhades and Tiia Kittil{\"a} and Christopher D. Fage and Robert J A Goode and Ralf B. Schittenhelm and Max J. Cryle},
  journal={The FEBS Journal},
The biosynthesis of the glycopeptide antibiotics (GPAs) demonstrates the exceptional ability of nonribosomal peptide (NRP) synthesis to generate diverse and complex structures from an expanded array of amino acid precursors. Whilst the heptapeptide cores of GPAs share a conserved C terminus, including the aromatic residues involved cross‐linking and that are essential for the antibiotic activity of GPAs, most structural diversity is found within the N terminus of the peptide. Furthermore, the… 

Redesign of substrate selection in glycopeptide antibiotic biosynthesis enables effective formation of alternate peptide backbones.

Here, it is explored and successfully reengineered the specificity of the module 3 A-domain from glycopeptide antibiotic biosynthesis to change the incorporation of 3,5-dihydroxyphenylglycine into 4-hydroxyphensyl glycine.

Genomic-Led Discovery of a Novel Glycopeptide Antibiotic by Nonomuraea coxensis DSM 45129

The strain produces a novel GPA, which is proposed is an A40926 analogue lacking the carboxyl group on the N-acylglucosamine moiety, which highlights genus Nonomuraea as a still untapped source of novel GPAs.

Exploring modular reengineering strategies to redesign the teicoplanin non-ribosomal peptide synthetase†

Using the relocation or exchange of domains within the NRPS modules, how to initiate peptide biosynthesis is identified and the requirements for the functional reengineering of both the condensation/adenylation domain and epimerisation/condensation domain interfaces are explored.

An Engineered Nonribosomal Peptide Synthetase Shows Opposite Amino Acid Loading and Condensation Specificity

A tool for investigating poorly accessible C-domain specificity through nonlinear kinetic modeling is established and critical insights how the interplay of A- and C-domains determines the product specificity of NRPSs are gained.

Biotechnological production optimization of argyrins – a potent immunomodulatory natural product class

The optimized system presented herein provides a versatile platform for production of this promising class of immunosuppressants at a scale that should provide sufficient supply for upcoming pre‐clinical development.

Functional Cross-Talk of MbtH-Like Proteins During Thaxtomin Biosynthesis in the Potato Common Scab Pathogen Streptomyces scabiei

Structural analysis of TxtH in association with the TxtA and TxtB adenylation domains revealed that several such residues are situated at the predicted interaction interface, suggesting that they might be critical for promoting functional interactions between MLPs and the thaxtomin NRPS enzymes.

Nyuzenamide C, an Antiangiogenic Epoxy Cinnamic Acid-Containing Bicyclic Peptide from a Riverine Streptomyces sp.

A new nonribosomal peptide, nyuzenamide C (1), was discovered from riverine sediment-derived Streptomyces sp. DM14. Comprehensive analysis of the spectroscopic data of nyuzenamide C (1) revealed that

Comparative genomics and transcriptomics analyses provide insights into the high yield and regulatory mechanism of Norvancomycin biosynthesis in Amycolatopsis orientalis NCPC 2-48

The results suggested that the high yield of NCPC 2-48 can be ascribed to increased expression level of norvancomycin biosynthetic genes in its cluster as well as the genes responsible for the supply of its precursors.

Anti-Cancer Activity of Gabapentin and Chiral Amino Acids-Based Hybrid-Peptides against MCF-7 Breast Cancer Cell-Line

The study showed that the compounds with some specific functionalities like, benzylic and trifluoromethyl functionality enhanced the potency with comparable %cell proliferation and cell death.



X-domain of peptide synthetases recruits oxygenases crucial for glycopeptide biosynthesis

It is shown that the presentation of peptidyl carrier protein (PCP)-bound substrates for oxidation in GPA biosynthesis requires the presence of the NRPS X-domain to ensure conversion of the precursor peptide into a mature aglycone, and that the carrier protein domain alone is not always sufficient to generate a competent substrate for external cytochrome P450 oxygenases.

Structure of a bound peptide phosphonate reveals the mechanism of nocardicin bifunctional thioesterase epimerase-hydrolase half-reactions

High-resolution crystal structures of the nocardicin thioesterase domain in ligand-free form are determined and reacted with a structurally precise fluorophosphonate substrate mimic that identify the complete peptide binding pocket to accommodate both stereoisomers of NocTE.

F-O-G Ring Formation in Glycopeptide Antibiotic Biosynthesis is Catalysed by OxyE

This work demonstrates that complex enzymatic cascades from glycopeptide antibiotic biosynthesis can be reconstituted in vitro and provides new insights into the biosynthesis of these important antibiotics.

Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics

The authors obtained a crystal structure of the kistamicin OxyA/X-domain complex and analysed the cyclisation cascade leading to the formation of the A-O-B ring, showing that the kistsicin OxyC enzyme is a promiscuous biocatalyst, able to install multiple crosslinks into peptides containing phenolic amino acids.

A chemoenzymatic approach to the synthesis of glycopeptide antibiotic analogues.

It is shown that the combination of peptide synthesis with enzymatic cyclisation enables the formation of novel examples of GPAs and provides an indication of the utility of these crucial enzymes.

Sequential In Vitro Cyclization by Cytochrome P450 Enzymes of Glycopeptide Antibiotic Precursors Bearing the X-Domain from Nonribosomal Peptide Biosynthesis.

It is demonstrated that sequential in vitro P450-catalyzed cyclization of peptide substrates is enabled by the use of an NRPS peptide carrier protein (PCP)-X di-domain as a P450 recruitment platform.

Structures of a Nonribosomal Peptide Synthetase Module Bound to MbtH-like Proteins Support a Highly Dynamic Domain Architecture*

The structures of the full-length NRPS EntF bound to the MLPs from Escherichia coli and Pseudomonas aeruginosa are presented and highlight the dynamic behavior of NRPS modules, including the module core formed by the adenylation and condensation domains as well as the orientation of the mobile thioesterase domain.

Structural and mutational analysis of the nonribosomal peptide synthetase heterocyclization domain provides insight into catalysis

The crystal structure of a Cy domain is presented, and accompanying mutagenic and bioinformatics analyses, uncover the importance of an aspartate and a threonine for the cyclodehydration reaction and provides insight into the catalysis of condensation by the Cy domain and enables the proposal of a reaction mechanism for cyclodeHydration.

Phylogenetic analysis of condensation domains in NRPS sheds light on their functional evolution

The reconstruction of the phylogenetic relationship of NRPS C domain subtypes is reported and the sequence motifs of recently discovered subtypes (Dual E/C, DCL and Starter domains) and their characteristic sequence differences are analyzed, mutually and in comparison with LCL domains.