The Biosynthesis of Vancomycin‐Type Glycopeptide Antibiotics—A Model for Oxidative Side‐Chain Cross‐Linking by Oxygenases Coupled to the Action of Peptide Synthetases

Bischoff, Daniel; Bister, Bojan; Bertazzo, Marcelo; Pfeifer, Volker; Stegmann, Efthimia; Nicholson, Graeme; Keller, Simone; Pelzer, Stefan; Wohlleben, Wolfgang; Süssmuth, Roderich D.

doi:10.1002/cbic.200400328

Cited by 114 publications

(113 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…During peptide formation, the aromatic residues are connected due to the activity of P450 monooxygenases (Oxy) to form a rigid cupshaped structure (41,42) required for the interaction with their molecular target, the D-alanyl-D-alanine (D-Ala-D-Ala) terminus of bacterial cell wall precursors. The A. japonicum glycopeptide gene cluster contains four oxy genes (orf28 to orf25), putatively encoding P450 monooxygenases, as within the teicoplanin, A47934, and dalbavancin gene clusters, all characterized by a fully cyclized heptapeptide backbone (22).…”

Section: Resultsmentioning

confidence: 99%

Overproduction of Ristomycin A by Activation of a Silent Gene Cluster in Amycolatopsis japonicum MG417-CF17

Spohn

Kirchner

Kulik

et al. 2014

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

eThe emergence of antibiotic-resistant pathogenic bacteria within the last decades is one reason for the urgent need for new antibacterial agents. A strategy to discover new anti-infective compounds is the evaluation of the genetic capacity of secondary metabolite producers and the activation of cryptic gene clusters (genome mining). One genus known for its potential to synthesize medically important products is Amycolatopsis. However, Amycolatopsis japonicum does not produce an antibiotic under standard laboratory conditions. In contrast to most Amycolatopsis strains, A. japonicum is genetically tractable with different methods. In order to activate a possible silent glycopeptide cluster, we introduced a gene encoding the transcriptional activator of balhimycin biosynthesis, the bbr gene from Amycolatopsis balhimycina (bbr Aba ), into A. japonicum. This resulted in the production of an antibiotically active compound. Following whole-genome sequencing of A. japonicum, 29 cryptic gene clusters were identified by genome mining. One of these gene clusters is a putative glycopeptide biosynthesis gene cluster. Using bioinformatic tools, ristomycin (syn. ristocetin), a type III glycopeptide, which has antibacterial activity and which is used for the diagnosis of von Willebrand disease and Bernard-Soulier syndrome, was deduced as a possible product of the gene cluster. Chemical analyses by high-performance liquid chromatography and mass spectrometry (HPLC-MS), tandem mass spectrometry (MS/MS), and nuclear magnetic resonance (NMR) spectroscopy confirmed the in silico prediction that the recombinant A. japonicum/pRM4-bbr Aba synthesizes ristomycin A.

show abstract

Section: Resultsmentioning

confidence: 99%

Overproduction of Ristomycin A by Activation of a Silent Gene Cluster in Amycolatopsis japonicum MG417-CF17

Spohn

Kirchner

Kulik

et al. 2014

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…The Oxy enzymes catalyze a critical step, probably the most distinctive feature in glycopeptide biosynthesis. Current evidence indicates that at least some of the Oxy enzymes act in concert with the NRPS while the growing peptide is still enzyme bound (3,36,46). In all glycopeptide clusters characterized to date, the oxy genes are linked and an oxyA ortholog is always the first gene, suggesting the existence of an operon in all cases.…”

Section: Discussionmentioning

confidence: 99%

Phosphate-Controlled Regulator for the Biosynthesis of the Dalbavancin Precursor A40926

et al. 2007

View full text Add to dashboard Cite

The actinomycete Nonomuraea sp. strain ATCC 39727 produces the glycopeptide A40926, the precursor of the novel antibiotic dalbavancin. Previous studies have shown that phosphate limitation results in enhanced A40926 production. The A40926 biosynthetic gene (dbv) cluster, which consists of 37 genes, encodes two putative regulators, Dbv3 and Dbv4, as well as the response regulator (Dbv6) and the sensor-kinase (Dbv22) of a putative two-component system. Reverse transcription-PCR (RT-PCR) and real-time RT-PCR analysis revealed that the dbv14-dbv8 and the dbv30-dbv35 operons, as well as dbv4, were negatively influenced by phosphate. Dbv4 shows a putative helix-turn-helix DNA-binding motif and shares sequence similarity with StrR, the transcriptional activator of streptomycin biosynthesis in Streptomyces griseus. Dbv4 was expressed in Escherichia coli as an N-terminal His 6 -tagged protein. The purified protein bound the dbv14 and dbv30 upstream regions but not the region preceding dbv4. Bbr, a Dbv4 ortholog from the gene cluster for the synthesis of the glycopeptide balhimycin, also bound to the dbv14 and dbv30 upstream regions, while Dbv4 bound appropriate regions from the balhimycin cluster. Our results provide new insights into the regulation of glycopeptide antibiotics, indicating that the phosphate-controlled regulator Dbv4 governs two key steps in A40926 biosynthesis: the biosynthesis of the nonproteinogenic amino acid 3,5-dihydroxyphenylglycine and critical tailoring reactions on the heptapeptide backbone.

show abstract

“…In these NRPS-biosynthesised heptapeptides, the three (vancomycin-type) or four (teicoplanin-type) crosslinks have been demonstrated to be inserted in vivo by cytochrome P450 enzymes, with each ring installed by a specic P450. [244][245][246][247][248] Furthermore, gene disruption experiments determined that a specic order of ring installation occurs during GPA biosynthesis (Fig. 21B).…”

mentioning

confidence: 99%

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

et al. 2018

View full text Add to dashboard Cite

The cytochromes P450 (P450s) are a superfamily of heme-containing monooxygenases that perform diverse catalytic roles in many species, including bacteria. The P450 superfamily is widely known for the hydroxylation of unactivated C-H bonds, but the diversity of reactions that P450s can perform vastly exceeds this undoubtedly impressive chemical transformation. Within bacteria, P450s play important roles in many biosynthetic and biodegradative processes that span a wide range of secondary metabolite pathways and present diverse chemical transformations. In this review, we aim to provide an overview of the range of chemical transformations that P450 enzymes can catalyse within bacterial secondary metabolism, with the intention to provide an important resource to aid in understanding of the potential roles of P450 enzymes within newly identified bacterial biosynthetic pathways. 1.Introduction to P450s 2.Chemistry of P450 enzymes 3.Bacterial biosynthesis pathways involving P450s 3.1Terpene metabolism 3.1. Battersby (1925Battersby ( -2018 to the molecular understanding of biosynthesis over the course of their careers.

show abstract

The Biosynthesis of Vancomycin‐Type Glycopeptide Antibiotics—A Model for Oxidative Side‐Chain Cross‐Linking by Oxygenases Coupled to the Action of Peptide Synthetases

Cited by 114 publications

References 26 publications

Overproduction of Ristomycin A by Activation of a Silent Gene Cluster in Amycolatopsis japonicum MG417-CF17

Overproduction of Ristomycin A by Activation of a Silent Gene Cluster in Amycolatopsis japonicum MG417-CF17

Phosphate-Controlled Regulator for the Biosynthesis of the Dalbavancin Precursor A40926

Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

Contact Info

Product

Resources

About