Biosynthesis of Xyrrolin, a New Cytotoxic Hybrid Polyketide/Non‐ribosomal Peptide Pyrroline with Anticancer Potential, in <i>Xylaria</i> sp. BCC 1067

Phonghanpot, Suranat; Punya, Juntira; Tachaleat, Anuwat; Laoteng, Kobkul; Bhavakul, Vanida; Tanticharoen, Morakot; Cheevadhanarak, Supapon

doi:10.1002/cbic.201100746

Cited by 18 publications

(14 citation statements)

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“…Furthermore, the Xylaria genus is a well studied source of secondary metabolites derived from a variety of biosynthetic pathways, 16 including polyketides, 17 non-ribosomal peptides, 18 and terpenoids. 19 Therefore, even phylogenetically unremarkable organisms isolated from tropical plants may enable discovery of new structures.…”

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confidence: 99%

Xyolide, a bioactive nonenolide from an Amazonian endophytic fungus, Xylaria feejeensis

Baraban

Morin

Phillips

et al. 2013

Tetrahedron Letters

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Endophytes isolated from tropical plants represent a largely untapped reservoir of bioactive secondary metabolites. We screened a library of fungal endophyte extracts for inhibition of the plant pathogen, Pythium ultimum, and purified an active compound using bioassay-guided fractionation. A new nonenolide, (4S,7S,8S,9R)-4-O-succinyl-7,8-dihydroxy-9-heptyl-nonen-9-olide, was isolated and named xyolide. The structure was elucidated by a combination of 1D and 2D NMR methods and the absolute configuration was determined by exciton-coupled circular dichroism. The MIC of xyolide against P. ultimum was 425 µM. KeywordsNatural product; Nonenolide; Fungal endophyte; Pythium ultimum Natural products have a rich history as pharmaceutical agents and biological probes. 1 Microorganisms have been an abundant source of biologically active natural products, but in recent years the discovery of new compounds has declined and, in some enterprises, the rediscovery rate has approached 99%. 2 Our goal is to identify new reservoirs of biodiversity likely to contain novel, bioactive natural products. Recent studies in our group indicate that microorganisms residing within tropical plants feature promising phylogenetic diversity and bioactivity. To identify organisms, we sequenced the internal transcribed spacer (ITS), a useful phylogenetic marker that lies between rRNA genes. Out of 135 endophytes isolated from plants collected in Peru and Bolivia, 10 featured ITS sequences that diverged deeply (<85% similarity) from known © 2013 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +0-203-432-9119; fax: +0-203-432-6161; jo.handelsman@yale.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supplementary dataSupplementary data, including experimental procedures and spectroscopic data for compounds 1 and 1a, can be found, in the online version. Given their ecological niche, we reasoned that endophytes might produce compounds that inhibit plant infection by pathogens. Therefore, we screened our collection of Amazonian endophytes for inhibition of growth of Pythium ultimum, an oomycete plant pathogen. NIH Public AccessOomycetes are lower eukaryotes, most closely related to the golden-brown algae, which infect major food crops, causing annual losses estimated in the billions of dollars. 4 P. insidiosum is pathogenic to mammals, including horses and humans. Currently available drugs are often ineffective against P. insidiosum, which lacks certain targets typical of other eukaryotic pathogens, such as fungi. 5 Thus, improving control of oomycetes is a high priority for practitione...

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confidence: 99%

Xyolide, a bioactive nonenolide from an Amazonian endophytic fungus, Xylaria feejeensis

Baraban

Morin

Phillips

et al. 2013

Tetrahedron Letters

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“…While originally searching for the gene cluster responsible for the production of 19,20‐epoxycytochalasin Q from the wood‐decay fungus Xylaria sp. BCC 1067,96 the novel PK–AA hybrid xyrrolin was identified 97. Deletion of pks3 , the only gene reported to encode a PKS–NRPS hybrid in the producer strain, abolished xyrrolin production.…”

Section: Xyrrolinmentioning

confidence: 99%

“…Unlike other PKS–NRPS hybrids, a terminal R/D domain is absent in PKS3, and the exact product‐release mechanism has not been determined. However, a Dieckmann‐type release would theoretically require one more keto group in the polyketide chain than that for a reductive release 97…”

Section: Xyrrolinmentioning

confidence: 99%

Molecular Diversity Sculpted by Fungal PKS–NRPS Hybrids

2012

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Fungal polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrids manufacture a wide range of structurally diverse secondary metabolites that play an eminent role in the environment, as molecular tools and leads for therapeutic development. To date, a dozen PKS-NRPS megasynthetases can be linked to the corresponding secondary metabolites, which stand out because of their structural complexity. The diversity of their structures, biological activities, and biosynthetic routes are particularly intriguing considering the iterative use of the catalytic domains of the biosynthetic enzymes-implying an enigmatic biosynthetic code. This review provides an overview of the characterized fungal PKS-NRPS hybrids, their manifold functionalities, and the diversity of the resulting secondary metabolites, as well as molecular engineering attempts that highly improved the understanding of their cryptic programming.

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“…Sequence analyses of fungal genomes have uncovered a high number of putative biosynthetic gene clusters including PKS–NRPS hybrid genes 8. Nevertheless, to date, the production of only a dozen fungal polyketide–amino acid hybrid molecules have been linked to the requisite gene cluster 9–13. Important examples of fungal hybrid PKS–NRPS metabolites include pyridones and tetramic acid derivatives such as cytochalasins, agents that specifically destroy the actin skeleton;14 the mycotoxins fusarin C,9 aspyridone,10 isoflavipucine12 and cyclopiazonic acid;15 tenellin,16 a pigment of an insect pathogen; the immunoglobulin E suppressor pseurotin;17 and the HIV‐1 integrase inhibitor equisetin 18…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Imprint of Catalytic Domains in Fungal PKS–NRPS Hybrids

et al. 2012

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Fungal hybrid enzymes consisting of a polyketide synthase (PKS) and a nonribosomal peptide synthetase (NRPS) module are involved in the biosynthesis of a vast array of ecologically and medicinally relevant natural products. Whereas a dozen gene clusters could be assigned to the requisite PKS-NRPS pathways, the programming of the multifunctional enzymes is still enigmatic. Through engineering and heterologously expressing a chimera of PKS (lovastatin synthase, LovB) and NRPS (cytochalasin synthase, CheA) in Aspergillus terreus, we noted the potential incompatibility of a fungal highly reducing PKS (hrPKS) with the NRPS component of fungal PKS-NRPS hybrids. To rationalize the unexpected outcome of the gene fusion experiments, we conducted extensive bioinformatic analyses of fungal PKS-NRPS hybrids and LovB-type PKS. From motif studies and the function of the engineered chimeras, a noncanonical function of C-terminal condensation (C) domains in truncated PKS-NRPS homologues was inferred. More importantly, sequence alignments and phylogenetic trees revealed an evolutionary imprint of the PKS-NRPS domains, which reflect the evolutionary history of the entire megasynthase. Furthermore, a detailed investigation of C and adenylation (A) domains provides support for a scenario in which not only the A domain but also the C domain participates in amino acid selection. These findings shed new light on the complex code of this emerging class of multifunctional enzymes and will greatly facilitate future combinatorial biosynthesis and pathway engineering approaches towards natural product analogues.

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Biosynthesis of Xyrrolin, a New Cytotoxic Hybrid Polyketide/Non‐ribosomal Peptide Pyrroline with Anticancer Potential, in Xylaria sp. BCC 1067

Cited by 18 publications

References 47 publications

Xyolide, a bioactive nonenolide from an Amazonian endophytic fungus, Xylaria feejeensis

Xyolide, a bioactive nonenolide from an Amazonian endophytic fungus, Xylaria feejeensis

Molecular Diversity Sculpted by Fungal PKS–NRPS Hybrids

Evolutionary Imprint of Catalytic Domains in Fungal PKS–NRPS Hybrids

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