Angucycline Group Research Articles

Diversity of Polyketide Synthases and Nonribosomal Peptide Synthetases Revealed Through Metagenomic Analysis of a Deep Oligotrophic Cave.

Caves are considered to be extreme and challenging environments. It is believed that the ability of microorganisms to produce secondary metabolites enhances their survivability and adaptiveness in the energy-starved cave environment. Unfortunately, information on the genetic potential for the production of secondary metabolites, such as polyketides and nonribosomal peptides, is limited. In the present study, we aimed to identify and characterize genes responsible for the production of secondary metabolites in the microbial community of one of the deepest caves in the world, Krubera-Voronja Cave (43.4184 N 40.3083 E, Western Caucasus). The analysed sample materials included sediments, drinkable water from underground camps, soil and clay from the cave walls, speleothems and coloured spots from the cave walls. The type II polyketide synthases (PKSs) ketosynthases α and β and the adenylation domains of nonribosomal peptide synthetases (NRPSs) were investigated using a metagenomic approach. Taxonomic diversity analysis showed that most PKS sequences could be attributed to Actinobacteria followed by unclassified bacteria and Acidobacteria, while the NRPS sequences were more taxonomically diverse and could be assigned to Proteobacteria, Actinobacteria, Cyanobacteria, Firmicutes, Chloroflexi, etc. Only three putative metabolites could be predicted: an angucycline group polyketide, a massetolide A-like cyclic lipopeptide and a surfactin-like lipopeptide. The absolute majority of PKS and NRPS sequences showed low similarity with the sequences of the reference biosynthetic pathways, suggesting that these sequences could be involved in the production of novel secondary metabolites.

THE ROLE OF REACTIVE OXYGEN SPECIES IN TUMOR CELLS APOPTOSIS INDUCED BY LANDOMYCIN A.

Landomycin A (LA) is a new antitumor antibiotic of angucycline group, possessing high antitumor activity against cancer cells of different origin, which induces early apoptosis in target cells. It was shown that under LA action the level of reactive oxygen species (ROS) in human T-leukemia cells had increased 5.6 times in comparison to control already at the 1st hour after the addition of studied antibiotic to the culture medium. At the 6th hour after incubation of cells with LA the nucleosomal DNA cleavage, chromatin condensation and nucleus fragmentation were observed, indicating apoptotic cell death. Catalase (scavenger of hydrogen peroxide), mannitol (scavenger of hydroxyl radicals) and superoxide dismutase (scavenger of superoxide radicals) reduced the level of ROS production under LA, suggesting the generation of H2O2, OH* and O2- radicals, respectively. It was revealed that catalase and mannitol effectively inhibited LA-mediated tumor cell death, increasing 2.5 times the percentage of alive cells in comparison to LA. However, superoxide dismutase had no significant inhibitory effect on cytotoxic activity of LA, indicating the minor role of superoxide anions in the implementation of antitumor activity of this antibiotic. Combination of catalase, mannitol and superoxide dismutase with LA increased 4-fold the percentage of alive cells in comparison to the action of LA. Dynamics of ROS formation confirms that the increase of ROS is a very rapid process, but at the same time it is not a direct consequence of apoptosis triggering, mediated by mitochondria.

Delineation of gilvocarcin, jadomycin, and landomycin pathways through combinatorial biosynthetic enzymology

The exact sequence of events in biosyntheses of natural products is essential not only to understand and learn from nature's strategies and tricks to assemble complex natural products, but also for yield optimization of desired natural products, and for pathway engineering and muta-synthetic preparation of analogues of bioactive natural products. Biosyntheses of natural products were classically studied applying in vivo experiments, usually by combining incorporation experiments with stable-isotope labeled precursors with cross-feeding experiments of putative intermediates. Later genetic studies were dominant, which consist of gene cluster determination and analysis of gene inactivation experiments. From such studies various biosynthetic pathways were proposed, to a large extent just through in silico analyses of the biosynthetic gene clusters after DNA sequencing. Investigations of the complex biosyntheses of the angucycline group anticancer drugs landomycin, jadomycin and gilvocarcin revealed that in vivo and in silico studies were insufficient to delineate the true biosynthetic sequence of events. Neither was it possible to unambiguously assign enzyme activities, especially where multiple functional enzymes were involved. However, many of the intriguing ambiguities could be solved after in vitro reconstitution of major segments of these pathways, and subsequent systematic variations of the used enzyme mixtures. This method has been recently termed 'combinatorial biosynthetic enzymology'.

Angucyclines: Biosynthesis, mode-of-action, new natural products, and synthesis.

Covering: 1997 to 2010. The angucycline group is the largest group of type II PKS-engineered natural products, rich in biological activities and chemical scaffolds. This stimulated synthetic creativity and biosynthetic inquisitiveness. The synthetic studies used five different strategies, involving Diels-Alder reactions, nucleophilic additions, electrophilic additions, transition-metal mediated cross-couplings and intramolecular cyclizations to generate the angucycline frames. Biosynthetic studies were particularly intriguing when unusual framework rearrangements by post-PKS tailoring oxidoreductases occurred, or when unusual glycosylation reactions were involved in decorating the benz[a]anthracene-derived cores. This review follows our previous reviews, which were published in 1992 and 1997, and covers new angucycline group antibiotics published between 1997 and 2010. However, in contrast to the previous reviews, the main focus of this article is on new synthetic approaches and biosynthetic investigations, most of which were published between 1997 and 2010, but go beyond, e.g. for some biosyntheses all the way back to the 1980s, to provide the necessary context of information.

ChemInform Abstract: Three Novel Members of Angucycline Group from Streptomyces sp. N05WA963.

AbstractNew angucyclines (I) and the new anthracycline (II) possess antiproliferative effects on a panel of cancer cell lines.

A method to type the potential angucycline producers in actinomycetes isolated from marine sponges

Angucyclines are aromatic polyketides with antimicrobial, antitumor, antiviral and enzyme inhibition activities. In this study, a new pair of degenerate primers targeting the cyclase genes that are involved in the aromatization of the first and/or second ring of angucycline, were designed and evaluated in a PCR protocol targeting the jadomycin cyclase gene of Streptomyces venezuelae ISP5230. The identity of the target amplicon was confirmed by sequencing. After validation, the primers were used to screen 49 actinomycete isolates from three different marine sponges to identify putative angucycline producers. Seven isolates were positively identified using this method. Sequence analysis of the positive amplicons confirmed their identity as putative angucycline cyclases with sequence highly similar to known angucycline cyclases. Phylogenetic analysis clustered these positives into the angucycline group of cyclases. Furthermore, amplifications of the seven isolates using ketosynthase-specific primers were positive, backing the results using the cyclase primers. Together these results provided strong support for the presence of angucycline biosynthetic genes in these isolates. The specific primer set targeting the cyclase can be used to identify putative angucycline producers among marine actinobacteria, and aid in the discovery of novel angucyclines.

Three novel members of angucycline group from Streptomyces sp. N05WA963

Three novel members of angucycline family named N05WA963A (1), B (2) and D (4), together with a new anthracycline named N05WA963C (3) were isolated from the culture broth of Streptomyces sp. N05WA963. The structures were elucidated on the basis of comprehensive spectral data analysis. All four compounds have shown antiproliferative effects on a panel of cancer cell lines such as SW620, K-562, MDA-MB-231, YES-4, T-98 and U251SP.

Enzymatic Total Synthesis of Rabelomycin, an Angucycline Group Antibiotic

A one-pot enzymatic total synthesis of angucycline antibiotic rabelomycin was accomplished, starting from acetyl-CoA and malonyl-CoA, using a mixture of polyketide synthase (PKS) enzymes of the gilvocarcin, ravidomycin, and jadomycin biosynthetic pathways. The in vitro results were compared to in vivo catalysis using analogous sets of enzymes.

Rearrangements of cyclobutenones. Electrocyclic ring closure and thermal ring expansions of 3-allenyl- and 3-alkynyl-2-dienyl-4,4-dimethoxycyclobutenones.

Thermal rearrangements of 2-allenyl- and 2-alkynyl-3-(2-ethenylphenyl)-4,4-dimethoxycyclobutenones were studied. At ambient temperature, the allenyl compounds undergo an electrocyclic cascade to give bicyclo[4.2.0]octadienyl-fused cyclobutenones. These unusual tetracyclic cyclobutenones were shown to be viable synthetic precursors to benzo[a]anthracene-7,12-diones, compounds representing the framework of the angucycline group of naturally occurring antibiotics. In contrast, the 2-alkynylcyclobutenones are stable at ambient temperature but undergo a facile rearrangement at 110 degrees C (toluene) to give the previously unknown naphthalene derivatives, 1,2-dihydro-2,2-dimethoxy-1-(3-alkenylidene)naphtho[2,1-b]furans.

Investigations on the biosynthesis of the angucycline group antibiotics aquayamycin and the urdamycins A and B. Results from the structural analysis of novel blocked mutant products

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTInvestigations on the biosynthesis of the angucycline group antibiotics aquayamycin and the urdamycins A and B. Results from the structural analysis of novel blocked mutant productsJuergen Rohr, Monika Schoenewolf, Gyorgyi Udvarnoki, Klaus Eckardt, Gisbert Schumann, Christina Wagner, John M. Beale, and Steve D. SoreyCite this: J. Org. Chem. 1993, 58, 9, 2547–2551Publication Date (Print):April 1, 1993Publication History Published online1 May 2002Published inissue 1 April 1993https://doi.org/10.1021/jo00061a032RIGHTS & PERMISSIONSArticle Views286Altmetric-Citations32LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (501 KB) Get e-Alerts Get e-Alerts

Angucycline group antibiotics.

Angucycline group antibiotics.