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Journal of the American Chemical Society Oct 2019Aryl polyene (APE) pigments are a widely distributed class of bacterial polyketides. So far, little is known about the biosynthesis of these compounds, which are...
Aryl polyene (APE) pigments are a widely distributed class of bacterial polyketides. So far, little is known about the biosynthesis of these compounds, which are produced by a novel type II polyketide synthase (PKS). We have identified all enzymes involved in APE biosynthesis and determined their peculiar functions. The biosynthesis was reconstituted , and ACP-bound intermediates were assigned for each reaction step by HPLC-MS. Native mass spectrometry experiments identified four stable complexes: the acyl-carrier proteins ApeE and ApeF bound to the thioesterase ApeK, the dehydratases ApeI and ApeP, and the ketosynthase ApeO in complex with its chain-length factor ApeC. X-ray structures of the heterodimeric ApeO:ApeC and ApeI:ApeP complexes depict striking protein-protein interactions. Altogether, our study elucidated mechanistic aspects of APE biosynthesis that unifies elements of type II fatty acid and PKS systems, but in addition includes novel enzyme complexes.
Topics: Amino Acid Sequence; Biocatalysis; Models, Molecular; Pigments, Biological; Polyenes; Polyketide Synthases; Protein Conformation
PubMed: 30908039
DOI: 10.1021/jacs.8b10776 -
The Journal of Antibiotics Nov 2011A new polyene macrolide family, closely related to the pentaene macrolide antibiotic roflamycoin, was isolated from the both fermentation broth and biomass of...
A new polyene macrolide family, closely related to the pentaene macrolide antibiotic roflamycoin, was isolated from the both fermentation broth and biomass of Streptomyces durmitorensis wild-type strain MS405. The main compound was identified by NMR and Fourier transform ion cyclotron resonance mass spectrometry as 32,33-didehydroroflamycoin (1; DDHR). Additional four structurally related compounds were determined solely by MS analysis. DDHR induces cell death by apoptosis in various cancer cell lines as demonstrated by DNA fragmentation. Striking feature of DDHR is its internal fluorescence allowing visualization of labeled plasma membranes and internal membrane structures.
Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Membrane; Fluorescence; Humans; Macrolides; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Molecular Structure; Polyenes; Staining and Labeling; Streptomyces
PubMed: 21915134
DOI: 10.1038/ja.2011.81 -
Hindustan Antibiotics Bulletin 1981
Review
Topics: Animals; Anti-Bacterial Agents; Cholesterol; Fungi; Lipid Metabolism; Male; Muscle Contraction; Polyenes; Prostate; Testis
PubMed: 7031023
DOI: No ID Found -
Scientific Reports Aug 2021Aryl polyenes (APE) are one of the most widespread secondary metabolites among gram-negative bacteria. In Acinetobacter baumannii, strains belonging to the virulent...
Aryl polyenes (APE) are one of the most widespread secondary metabolites among gram-negative bacteria. In Acinetobacter baumannii, strains belonging to the virulent global clone 2 (GC2) mostly contain APE biosynthesis genes; its relevance in elevated pathogenicity is of great interest. APE biosynthesis gene clusters harbor two ketosynthases (KSs): the heterodimeric KS-chain length factor complex, ApeO-ApeC, and the homodimeric ketoacyl-acyl carrier protein synthase I (FabB)-like KS, ApeR. The role of the two KSs in APE biosynthesis is unclear. We determined the crystal structures of the two KSs from a pathogenic A. baumannii strain. ApeO-ApeC and ApeR have similar cavity volumes; however, ApeR has a narrow cavity near the entrance. In vitro assay based on the absorption characteristics of polyene species indicated the generation of fully elongated polyene with only ApeO-ApeC, probably because of the funnel shaped active site cavity. However, adding ApeR to the reaction increases the throughput of APE biosynthesis. Mutagenesis at Tyr135 in the active site cavity of ApeR reduces the activity significantly, which suggests that the stacking of the aryl group between Tyr135 and Phe202 is important for substrate recognition. Therefore, the two KSs function complementarily in the generation of APE to enhance its production.
Topics: Acinetobacter baumannii; Catalytic Domain; Mutagenesis; Polyenes; Polyketide Synthases
PubMed: 34381152
DOI: 10.1038/s41598-021-95890-y -
Journal of Cellular Physiology Aug 1979Cytotoxicity and membrane permeability alterations induced by the polyene macrolide antibiotics filipin (FIL) and pimaricin (PIM) have been compared in parental...
Cytotoxicity and membrane permeability alterations induced by the polyene macrolide antibiotics filipin (FIL) and pimaricin (PIM) have been compared in parental intraspecific and interspecific somatic cell hybrids. B82 (mouse) and B1 (hamster) cells were found to be more resistant than RAG (mouse) parental cells to both polyene macrolides as indicated by 24-hour survival, 72-hour viability, and growth rate. Analysis of both intraspecific and interspecific somatic cell hybrids indicated that polyene macrolide resistance was being expressed even in the presence of the polyene macrolide-sensitive (RAG) genome. Where one of the two parental cell types is relatively polyene macrolide resistant, the use of specific polyene macrolides may prove efficacious as half-selective agents in cell hybridization.
Topics: Animals; Cell Fusion; Cell Line; Cell Membrane; Cell Survival; Cricetinae; Dose-Response Relationship, Drug; Drug Resistance; Filipin; Hybrid Cells; Mice; Natamycin; Phenotype; Polyenes
PubMed: 315947
DOI: 10.1002/jcp.1041000214 -
Biochimica Et Biophysica Acta Aug 2014Polyene lipids and alkyne lipids allow study of lipid organization, dynamics and metabolism. Both types of lipids contain multiple bonds as the essential functional... (Review)
Review
Polyene lipids and alkyne lipids allow study of lipid organization, dynamics and metabolism. Both types of lipids contain multiple bonds as the essential functional group, leading to minimal disturbance of the hydrophobic properties on which the characteristic behavior of lipids is based. Polyene lipids can directly be traced due to their intrinsic fluorescence, while alkyne lipids need the copper-catalyzed click reaction to an azido-reporter for detection. This review describes recent developments in synthesis and application of both types of lipid analogs with emphasis on metabolic tracing and microscopy imaging. This article is part of a Special Issue entitled Tools to study lipid functions.
Topics: Alkynes; Hydrophobic and Hydrophilic Interactions; Lipids; Polyenes
PubMed: 24412758
DOI: 10.1016/j.bbalip.2013.12.018 -
Proceedings of the National Academy of... Nov 2016The bacteria harbored by fungus-growing ants produce a variety of small molecules that help maintain a complex multilateral symbiosis. In a survey of antifungal...
The bacteria harbored by fungus-growing ants produce a variety of small molecules that help maintain a complex multilateral symbiosis. In a survey of antifungal compounds from these bacteria, we discovered selvamicin, an unusual antifungal polyene macrolide, in bacterial isolates from two neighboring ant nests. Selvamicin resembles the clinically important antifungals nystatin A and amphotericin B, but it has several distinctive structural features: a noncationic 6-deoxymannose sugar at the canonical glycosylation site and a second sugar, an unusual 4-O-methyldigitoxose, at the opposite end of selvamicin's shortened polyene macrolide. It also lacks some of the pharmacokinetic liabilities of the clinical agents and appears to have a different target. Whole genome sequencing revealed the putative type I polyketide gene cluster responsible for selvamicin's biosynthesis including a subcluster of genes consistent with selvamicin's 4-O-methyldigitoxose sugar. Although the selvamicin biosynthetic cluster is virtually identical in both bacterial producers, in one it is on the chromosome, in the other it is on a plasmid. These alternative genomic contexts illustrate the biosynthetic gene cluster mobility that underlies the diversity and distribution of chemical defenses by the specialized bacteria in this multilateral symbiosis.
Topics: Actinobacteria; Animals; Antifungal Agents; Ants; Candida albicans; Gene Transfer, Horizontal; Genome, Bacterial; Genomics; Glycosylation; Macrolides; Multigene Family; Plasmids; Polyenes
PubMed: 27803316
DOI: 10.1073/pnas.1613285113 -
Organic Letters Jun 2019Heterologous expression of a unique biosynthetic gene cluster (BGC) comprising a highly reducing polyketide synthase and stand-alone thioesterase genes in Aspergillus...
Heterologous expression of a unique biosynthetic gene cluster (BGC) comprising a highly reducing polyketide synthase and stand-alone thioesterase genes in Aspergillus oryzae enabled us to isolate a novel 34-membered polyene macrolide, phaeospelide A (1). This is the first isolation of a fungal polyene macrolide and the first demonstration of fungal aliphatic macrolide biosynthetic machinery. In addition, sequence similarity network analysis demonstrated the existence of a large number of BGCs for novel fungal macrolides.
Topics: Aspergillus oryzae; Cyclization; Macrolides; Molecular Conformation; Polyenes; Polyketides; Thiolester Hydrolases; Trans-Activators
PubMed: 31180682
DOI: 10.1021/acs.orglett.9b01674 -
Journal of Natural Products May 2017Marine algae from the genus Karlodinium are known to be involved in fish-killing events worldwide. Here we report for the first time the chemistry and bioactivity of a...
Marine algae from the genus Karlodinium are known to be involved in fish-killing events worldwide. Here we report for the first time the chemistry and bioactivity of a natural product from the newly described mixotrophic dinoflagellate Karlodinium armiger. Our work describes the isolation and structural characterization of a new polyhydroxy-polyene named karmitoxin. The structure elucidation work was facilitated by use of C enrichment and high-field 2D NMR spectroscopy, where H-C long-range correlations turned out to be very informative. Karmitoxin is structurally related to amphidinols and karlotoxins; however it differs by containing the longest carbon-carbon backbone discovered for this class of compounds, as well as a primary amino group. Karmitoxin showed potent nanomolar cytotoxic activity in an RTgill-W1 cell assay as well as rapid immobilization and eventual mortality of the copepod Acartia tonsa, a natural grazer of K. armiger.
Topics: Amines; Animals; Dinoflagellida; Magnetic Resonance Spectroscopy; Marine Toxins; Molecular Structure; Polyenes
PubMed: 28379705
DOI: 10.1021/acs.jnatprod.6b00860 -
Organic Letters Feb 2011A previously unreported 26-membered polyene macrocyclic lactam, sceliphrolactam, was isolated from an actinomycete, Streptomyces sp., associated with the mud dauber,...
A previously unreported 26-membered polyene macrocyclic lactam, sceliphrolactam, was isolated from an actinomycete, Streptomyces sp., associated with the mud dauber, Sceliphron caementarium. Sceliphrolactam's structure was determined by 1D- and 2D-NMR, MS, UV, and IR spectral analysis. Sceliphrolactam displays antifungal activity against amphotericin B-resistant Candida albicans (MIC = 4 μg/mL, 8.3 μM).
Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Lactams, Macrocyclic; Microbial Sensitivity Tests; Nuclear Magnetic Resonance, Biomolecular; Polyenes; Streptomyces; Wasps
PubMed: 21247188
DOI: 10.1021/ol102991d