Understanding the crucial interactions between Cytochrome P450s and non-ribosomal peptide synthetases during glycopeptide antibiotic biosynthesis

The importance of Cytochrome P450-catalyzed modifications of natural products produced by non-ribosomal peptide synthetase machineries is most apparent during glycopeptide antibiotic biosynthesis: specifically, the formation of essential amino acid side chains crosslinks in the peptide backbone of these clinically relevant antibiotics. These cyclization reactions take place whilst the peptide substrate remains bound to the non-ribosomal peptide synthetase in a process mediated by a conserved domain of previously unknown function—the X-domain. This review addresses recent advances in understanding P450 recruitment to non-ribosomal peptide synthetase-bound substrates and highlights the importance of both carrier proteins and the X-domain in different P450-catalyzed reactions

Polyzyklische Makrolactone.

The invention relates to novel polycyclic macrolactones, which can be produced in particular by a representative of the bacteria genus Verrucosispora. Said substances are preferably characterised by their pharmacological action and exhibit in particular an antibiotic action. Preferably, said antibiotic action is active against gram-positive bacteria

Deuterium-Labeled Precursor Feeding Reveals a New pABA-Containing Meroterpenoid from the Mango Pathogen Xanthomonas citri pv. mangiferaeindicae

WOS: 000378758200007PubMed ID: 27232656A new para-aminobenzoic-acid-containing natural product from the mango pathogenic organism Xanthomonas citri pv. mangiferaeindicae is described. By means of stable isotope precursor feeding combined with nontargeted LC-MS/MS, the generated spectra were clustered and visualized in a molecular network. This led to the identification of a new member of the meroterpenoids, termed xanthomonic acid, which is composed of an isoprenylated Para-amino benzoic acid. In vitro cytotoxicity assays demonstrated activity of xanthomonic acid against several human cancer cell lines by induction of autophagy.German Academic Exchange Service (Deutscher Akademischer Austauschdienst)Deutscher Akademischer Austausch Dienst (DAAD); Egyptian Ministry of Higher EducationScience and Technology Development Fund (STDF)The authors thank Dr. Sebastian Kemper (Technical University of Berlin) for the instrumentation of the NMR experiments and Dr. P. Ballar Kirmizibayrak (Ege University) for support and guidance on the autophagy study. H.S. thanks the collaborative funding and support from the German Academic Exchange Service (Deutscher Akademischer Austauschdienst) and the Egyptian Ministry of Higher Education

Combined venom profiling and cytotoxicity screening of the Radde's mountain viper (Montivipera raddei) and Mount Bulgar Viper (Montivipera bulgardaghica) with potent cytotoxicity against human A549 lung carcinoma cells

WOS: 000407869000009PubMed ID: 28625888Here we report the first characterization of the endemic Mount Bulgar Viper (Montivipera bulgardaghica) and Radde's mountain viper (Montivipera raddei) venom by a combined approach using intact mass profiling and bottom-up proteomics. The cytotoxicity screening of crude venom as well as isolated serine proteases revealed a high activity against A549 human lung carcinoma cells. By means of intact mass profiling of native and reduced venom we observed basic and acidic phospholipases type A(2). Moreover, the analysis revealed snake venom metalloproteases, cysteine-rich secretory proteins, disintegrins, snake venom serine proteases, C-type lectins, a vascular endothelial growth factor and an L-amino acid oxidase. (C) 2017 Elsevier Ltd. All rights reserved.Deutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG); Cluster of Excellence Unifying Concepts in Catalysis (UniCat)German Research Foundation (DFG); Scientific and Technical Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [111T338]This study was supported by the Deutsche Forschungsgemeinschaft (DFG), Cluster of Excellence Unifying Concepts in Catalysis (UniCat) and by the Scientific and Technical Research Council of Turkey (TUBITAK) under Grant 111T338

Noursamycins, Chlorinated Cyclohexapeptides Identified from Molecular Networking of Streptomyces noursei NTR-SR4.

Mudalungu CM, von Torne WJ, Voigt K, et al. Noursamycins, Chlorinated Cyclohexapeptides Identified from Molecular Networking of Streptomyces noursei NTR-SR4. Journal of natural products. 2019;82(6):1478-1486.The noursamycins A-F are chlorinated cyclic hexapeptides, which were identified and isolated from the strain Streptomyces noursei NTR-SR4 overexpressing a LuxR-like transcriptional activator. The molecules were structurally characterized by mass spectrometric analyses and 1D and 2D NMR spectroscopic techniques. The enzymatic machinery involved in the biosynthesis of these peptides is represented by a modular nonribosomal peptide synthetase (NRPS), and the corresponding gene cluster was identified in the S. noursei genome. The latter suggested the biosynthetic pathway for the noursamycins. Spectral networking analysis uncovered noursamycin derivatives that were later found to result from a relaxed substrate specificity of the A3 and A4 adenylation domains of the NRPS. The stereochemistry of the amino acid constituents of the noursamycins was resolved by chemical derivatization, subsequent enantiomer analytics by GC-EIMS, and in silico data analyses. Noursamycins A and B exhibited antibacterial activity against Gram-positive and Gram-negative bacteria, while no apparent cytotoxicity was observed

Abyssomicins, inhibitors of the para-aminobenzoic acid pathway produced by the marine Verrucosispora strain AB-18-032

A screening method was established to detect inhibitors of the biosynthetic pathways of aromatic amino acids and para-aminobenzoic acid, the precursor of folic acid, using an agar plate diffusion assay modified as an antagonism test. By this screening method, a family of three novel polycyclic polyketides named as abyssomicins was isolated from a marine strain of Verrucosispora. The main component abyssomicin C inhibits the pathway between chorismate and para-aminobenzoic acid and is strongly active against gram-positive bacteria, including multi-resistant clinical isolates of Staphylococcus aureus