Azaspirene:  A Novel Angiogenesis Inhibitor Containing a 1-Oxa-7-azaspiro[4.4]non-2-ene-4,6-dione Skeleton Produced by the Fungus <i>Neosartorya</i> sp.

Asami, Yukihiro; Kakeya, Hideaki; Onose, Rie; Yoshida, Arika; Matsuzaki, Hiroshi; Osada, Hiroyuki

doi:10.1021/ol020104+

Cited by 132 publications

(64 citation statements)

References 17 publications

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“…[12,13,14] Azaspirene (4), with the same core structure, was obtained from A C H T U N G T R E N N U N G Neosartorya sp. [15] Pseurotin A is derived from l-phenylalanine, propionate, malonate and l-methionine, as proven by feeding experiments with 13 C-labelled precursors. [16] The structure and biosynthetic origin of pseurotin A suggests the involvement of a hybrid PKS/NRPS.…”

Section: Bioinformaticsmentioning

confidence: 99%

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Identification of a Hybrid PKS/NRPS Required for Pseurotin A Biosynthesis in the Human Pathogen Aspergillus fumigatus

et al. 2007

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The genome sequence of Aspergillus fumigatus revealed the presence of a single hybrid polyketide synthase-non-ribosomal peptide synthetase (PKS/NRPS) gene that is present within a cluster of five genes suggestive of its involvement in secondary metabolism. Here, we present evidence that it is required for the biosynthesis of pseurotin A, a compound with an unusual heterospirocyclic gamma-lactam structure. We have confirmed that the genome reference strain A. fumigatus Af293 produces pseurotin A, a compound previously reported to be a competitive inhibitor of chitin synthase and an inducer of nerve-cell proliferation. Deletion or overexpression of the PKS/NRPS gene psoA in A. fumigatus leads to the absence or accumulation of pseurotin A, respectively; this indicates that this gene is essential for the biosynthesis of pseurotin A. It is likely that the first product of psoA is converted to pseurotin A by the products of other genes in this cluster.

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Section: Bioinformaticsmentioning

confidence: 99%

“…The cDNA was prepared by using First-Strand cDNA synthesis kit (Amersham Biosciences; 1 mg RNA per 15 mL reaction mixture). RNA was treated with DNase I (Roche) prior to cDNA synthesis 15 primer (1 mL, Amersham Biosciences) according to the manufacturer's instructions. The cDNA made was purified by using a PCR purification kit (QIAGEN).…”

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confidence: 99%

Identification of a Hybrid PKS/NRPS Required for Pseurotin A Biosynthesis in the Human Pathogen Aspergillus fumigatus

et al. 2007

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“…As discussed earlier, structural diversity of natural products is likely generated during the post-PKS-NRPS modification steps. We expected this to be the case with the pseurotin-type of natural products, which includes biologically active molecules like azaspirene (20), 73) synerazol (21) [74][75][76] and cephalimysin A (23) 69) that vary in C-and O-methylations and the extent of oxidation (Chart 7). Thus, methylation and oxidation steps were investigated using strains carrying deletion of the genes predicted to encode methyltransferase, FMO and P450 found in the cluster, namely psoC, psoD, psoE and psoF.…”

Section: Understanding Pseurotin Scaffold By Functional Analysis Of Tmentioning

confidence: 99%

Effective Use of Heterologous Hosts for Characterization of Biosynthetic Enzymes Allows Production of Natural Products and Promotes New Natural Product Discovery

Watanabe

2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the past few years, there has been impressive progress in elucidating the mechanism of biosynthesis of various natural products accomplished through the use of genetic, molecular biological and biochemical techniques. Here, we present a comprehensive overview of the current results from our studies on fungal natural product biosynthetic enzymes, including nonribosomal peptide synthetase and polyketide synthasenonribosomal peptide synthetase hybrid synthetase, as well as auxiliary enzymes, such as methyltransferases and oxygenases. Specifically, biosynthesis of the following compounds is described in detail: (i) Sch210972, potentially involving a Diels-Alder reaction that may be catalyzed by CghA, a functionally unknown protein identified by targeted gene disruption in the wild type fungus; (ii) chaetoglobosin A, formed via multi-step oxidations catalyzed by three redox enzymes, one flavin-containing monooxygenase and two cytochrome P450 oxygenases as characterized by in vivo biotransformation of relevant intermediates in our engineered Saccharomyces cerevisiae; (iii) ( )-ditryptophenaline, formed by a cytochrome P450, revealing the dimerization mechanism for the biosynthesis of diketopiperazine alkaloids; (iv) pseurotins, whose variations in the Cand O-methylations and the degree of oxidation are introduced combinatorially by multiple redox enzymes; and (v) spirotryprostatins, whose spiro-carbon moiety is formed by a flavin-containing monooxygenase or a cytochrome P450 as determined by heterologous de novo production of the biosynthetic intermediates and final products in Aspergillus niger. We close our discussion by summarizing some of the key techniques that have facilitated the discovery of new natural products, production of their analogs and identification of biosynthetic mechanisms in our study.

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“…[1] Kakeya, Osada and co-workers have isolated and determined the structures of epoxyquinols A (1), [2] B (2), [3] and C (3) [4] and epoxytwinol A (4) [5] from an unknown soil fungus, and azaspirene [6] and RK-805 [7] from the fungus Neosartorya sp. (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Chemistry of Epoxyquinols A, B, and C and Epoxytwinol A

Shoji

Hayashi

2007

Eur J Org Chem

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The asymmetric total synthesis of epoxyquinols A, B, and C and epoxytwinol A, and computational analysis of the key biomimetic oxidative dimerization procedure are described. In the first-generation synthesis, a HfCl 4 -mediated diastereoselective Diels-Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan and a lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale synthesis.

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Azaspirene: A Novel Angiogenesis Inhibitor Containing a 1-Oxa-7-azaspiro[4.4]non-2-ene-4,6-dione Skeleton Produced by the Fungus Neosartorya sp.

Abstract: [structure: see text] Azaspirene isolated from the fungus Neosartorya sp. is a novel angiogenesis inhibitor with a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton. Azaspirene inhibits the endothelial migration induced by vascular endothelial growth factor (ED100 = 27.1 microM).

Cited by 132 publications

References 17 publications

Identification of a Hybrid PKS/NRPS Required for Pseurotin A Biosynthesis in the Human Pathogen Aspergillus fumigatus

Identification of a Hybrid PKS/NRPS Required for Pseurotin A Biosynthesis in the Human Pathogen Aspergillus fumigatus

Effective Use of Heterologous Hosts for Characterization of Biosynthetic Enzymes Allows Production of Natural Products and Promotes New Natural Product Discovery

Chemistry of Epoxyquinols A, B, and C and Epoxytwinol A

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