Biosynthetic incorporation of labeled tetraketide intermediates into dehydrocurvularin, a phytotoxin from Alternaria cinerariae, with assistance of .beta.-oxidation inhibitors

Li, Zhe; Martin, Fionna M.; Vederas, John C.

doi:10.1021/ja00030a088

Cited by 40 publications

(24 citation statements)

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“…The 2D-NMR analysis (HMQC and HMBC experiments) of this molecule remains incomplete because of the unfavourable ratio of quaternary carbon to hydrogen-binding carbon atoms. This fact, together with some overlapping 13 C-NMR shifts, led to the result that only 19 of 27 13 C-NMR signals could definitely be assigned.…”

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confidence: 94%

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Structural and Biosynthetic Investigations of the Rubromycins

et al. 2000

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The structure of the known secondary metabolite β‐rubromycin was corrected, based on spectroscopic and chemical investigations, from o‐quinone 1 to p‐quinone 6. By feeding [U‐13C3]malonic acid to the rubromycin‐producing strain, Streptomyces sp. A1, the polyketide origin of the skeleton was verified, but the identity of the starter unit and the folding mechanism of the polyketide chain are still unclear. From the culture broth of the strain A1, in addition to 6, the co‐metabolites γ‐rubromycin (3), δ‐rubromycin (4) and 3′‐hydroxy‐β‐rubromycin (7) were isolated. Their structures were determined or confirmed by detailed spectroscopic analysis. The rubromycins inhibit HIV‐1 reverse transcriptase (RT) and are cytostatically active against different tumor cell lines.

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confidence: 94%

“…Further problems arose with the assignment of the 13 C-NMR data of β-rubromycin for the biosynthetic studies. The 2D-NMR analysis (HMQC and HMBC experiments) of this molecule remains incomplete because of the unfavourable ratio of quaternary carbon to hydrogen-binding carbon atoms.…”

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confidence: 99%

Structural and Biosynthetic Investigations of the Rubromycins

et al. 2000

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“…The cultures were grown for an additional 9 h, and another 500 l of a suspension of [1,2,3,4-13 C 4 ]octanoic acid (125 mg in 5 ml 5% NaHCO 3 ) was added to each flask. To limit degradation of the labeled compound, 800 l of a 250 mM 3-mercaptopropionate solution (Sigma) was also added to each of the flasks at the same time (39). The cultures were grown for a total of 22 h at 28°C, and each entire culture was extracted twice with 500 ml of ethyl acetate.…”

Section: Methodsmentioning

confidence: 99%

2,5-Dialkylresorcinol Biosynthesis in Pseudomonas aurantiaca : Novel Head-to-Head Condensation of Two Fatty Acid-Derived Precursors

et al. 2003

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2-Hexyl-5-propylresorcinol is the predominant analog of several dialkylresorcinols produced by Pseudomonas aurantiaca (Pseudomonas fluorescens BL915). We isolated and characterized three biosynthetic genes that encode an acyl carrier protein, a ␤-ketoacyl-acyl carrier protein synthase III, and a protein of unknown function, all of which collectively allow heterologous production of 2-hexyl-5-propylresorcinol in Escherichia coli. Two regulatory genes exhibiting similarity to members of the AraC family of transcriptional regulators are also present in the identified gene cluster. Based on the deduced functions of the proteins encoded by the gene cluster and the observed incorporation of labeled carbons from octanoic acid into 2-hexyl-5-propylresorcinol, we propose that dialkylresorcinols are derived from medium-chain-length fatty acids by an unusual head-tohead condensation of ␤-ketoacyl thioester intermediates. Genomic evidence suggests that there is a similar pathway for the biosynthesis of the flexirubin-type pigments in certain bacteria belonging to the order Cytophagales.

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“…Carboxylic acid SNACs had been shown to act as water-soluble and membranepermeable mimics of carrier protein thioester precursors during in vitro and in vivo production of polyketides in recombinant and native producer systems (30,31,42,(55)(56)(57). Feeding 7(S)-hydroxyoct-2(E)-enoic acid SNAC (compound 15) to the S. cerevisiae BJ5464-NpgA strain expressing only AtcurS2 led to the in vivo production of 10,11-dehydrocurvularin (compound 1) and 11-hydroxycurvularin (compound 2), as expected (Fig.…”

Section: Isolation Of the Dehydrocurvularin Biosynthetic Locusmentioning

confidence: 99%

“…This polyketide occurs together with an epimeric mixture of 11-hydroxycurvularins (compound 2), formed as a result of the addition of water in potato dextrose broth medium (29). It was also shown that linear, reduced tetraketides and their N-acetylcysteamine thioester (SNAC) derivatives can be incorporated into curvularins (30,31). However, in spite of the structural similarities of RALs and DALs, it has been unknown whether DAL biosynthesis also employs collaborating and sequentially acting hrPKS-nrPKS pairs in fungi and thus whether the "chemical modularity" principle that is operational in RALs could also be extended to these molecules.…”

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confidence: 99%

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

Espinosa-Artiles

Schubert

et al. 2013

Appl Environ Microbiol

114

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d 10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta-or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides.

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Biosynthetic incorporation of labeled tetraketide intermediates into dehydrocurvularin, a phytotoxin from Alternaria cinerariae, with assistance of .beta.-oxidation inhibitors

Cited by 40 publications

References 0 publications

Structural and Biosynthetic Investigations of the Rubromycins

Structural and Biosynthetic Investigations of the Rubromycins

2,5-Dialkylresorcinol Biosynthesis in Pseudomonas aurantiaca : Novel Head-to-Head Condensation of Two Fatty Acid-Derived Precursors

Characterization of the Biosynthetic Genes for 10,11-Dehydrocurvularin, a Heat Shock Response-Modulating Anticancer Fungal Polyketide from Aspergillus terreus

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