Structure revision of the antibiotic echinomycin

Dell, Anne; Williams, Dudley H.; Morris, Howard R.; Smith, Gerald A.; Feeney, J.; Roberts, Gordon C. K.

doi:10.1021/ja00842a029

Cited by 328 publications

(128 citation statements)

References 2 publications

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“…Quinomycin class antibiotics, represented by echinomycin (1) 1 and SW-163D (2), [2][3][4] are C2-symmetric cyclic depsipeptides with a pair of intercalative chromophores that show potent antibacterial, anticancer and antiviral activities ( Figure 1). These antibiotics have potent DNA binding affinities at a level between nM and mM with different sequence selectivities.…”

Section: Introductionmentioning

confidence: 99%

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

et al. 2010

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Quinomycin antibiotics, represented by echinomycin, are an important class of antitumor antibiotics. We have recently succeeded in identification of biosynthetic gene clusters of echinomycin and SW-163D, and have achieved heterologous production of echinomycin in Escherichia coil. In addition, we have engineered echinomycin nonribosomal peptide synthetase (NRPS) to generate echinomycin derivatives. However, the biosynthetic pathways of intercalative chromophores quinoxaline-2-carboxylic acid (QXC) and 3-hydroxyquinaldic acid (HQA), which are important for biological activity, were not fully elucidated. Here, we report experiments involving incorporation of a putative advanced precursor, (2S, 3R)-[6'-2H]-3-hydroxy-L-kynurenine, and functional analysis of the enzymes Swb1 and Swb2 responsible for late-stage biosynthesis of HQA. Based on these experimental results, we propose biosynthetic pathways for both QXC and HQA via the common intermediate 3-hydroxy-L-kynurenine

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Section: Introductionmentioning

confidence: 99%

Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics

et al. 2010

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“…The triostins possess a simple disulfide crossbridge ( Fig. 1), whereas the quinomycins have a thioacetal linkage (3,15,17). Natural variants occur within each family in which the L-Nmethylvaline residues are replaced by other branched-chain amino acids (11).…”

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confidence: 99%

Preparation and DNA-binding properties of substituted triostin antibiotics

Cornish¹,

Fox²,

Waring³

1983

Antimicrob Agents Chemother

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Novel derivatives of the triostin group of antibiotics were prepared by supplementing cultures of the producing organism Streptomyces triostinicus with a variety of aromatic carboxylic acids. Five new antibiotics, each having both the natural quinoxaline chromophores replaced by a substituted ring system, were purified to homogeneity and characterized by high-pressure liquid chromatography and nuclear magnetic resonance. Their antibacterial activities and DNAbinding properties were investigated. Addition of a halogen atom at position 6 of the quinoxaline ring or an amino group at position 3 had little effect on either the biological activity or the DNA-binding characteristics. The bis-3-amino derivative is fluorescent, and its fluorescence is strongly quenched by calf thymus DNA and polydeoxyguanylate-polydeoxycytidylate but not by polydeoxyadenylatepolydeoxythymidylate, suggesting that it binds preferentially to guanosine-cytosine-rich sequences in natural DNA. Binding constants for the bis-6-chloro and bis-3-amino derivatives do not differ greatly from those of unsubstituted triostin A. The analogs having two quinoline chromophores or a chlorine atom in position 7 of the quinoxaline ring display little or no detectable antibacterial activity, in marked contrast to the other congeners. Bis-7-chloro-triostin A binds conspicuously more tightly to polydeoxyadenylate-polydeoxythymidylate than to any other polynucleotide tested.Quinoxaline antibiotics are produced by several species of streptomycetes. They are characterized by a heterodetic cyclic octadepsipeptide to which two quinoxaline-2-carboxylic acid chromophores are attached. Members of the group fall naturally into two families, the quinomycins and the triostins, which differ in the nature of the cross-bridge dividing the peptide ring into two quasi-symmetrical halves (11, 21). The triostins possess a simple disulfide crossbridge (Fig.

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“…Thus, the absolute configuration at the -position of N-methylcysteine and that in the thioacetal portion was determined as R. Our conclusion is identical to that predicted by the NMR data for the SW-163G (7)-DNA complex. 11) In addition, the stereochemistry of the SW-163 derivatives is similar to that of echinomycin (1). We have recently established that the disulfide bond in triostin A (2) was converted into the thioacetal moiety in echinomycin with methyl transferase Ecm18.…”

Section: Resultsmentioning

confidence: 98%