Natural products of filamentous fungi: enzymes, genes, and their regulation

Hoffmeister, Dirk; Keller, Nancy P.

doi:10.1039/b603084j

Cited by 500 publications

(325 citation statements)

References 280 publications

(233 reference statements)

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“…Natural products such as polyketides and nonribosomal peptides isolated from filamentous fungi have played indispensable roles in human health care (1). During the past decade, advances in rapid DNA sequencing techniques have enabled the complete genome sequencing of many fungi species (2)(3)(4)(5)(6).…”

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confidence: 99%

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Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

Tang

2010

Journal of Biological Chemistry

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The fungal iterative nonreducing polyketide synthases (NRPKSs) synthesize aromatic polyketides, many of which have important biological activities. The product template domains (PT) embedded in the multidomain NRPKSs mediate the regioselective cyclization of the highly reactive polyketide backbones and dictate the final structures of the products. Understanding the sequence-activity relationships of different PT domains is therefore an important step toward the prediction of polyketide structures from NRPKS sequences and can enable the genome mining of hundreds of cryptic NRPKSs uncovered via genome sequencing. In this work, we first performed phylogenetic analysis of PT domains from NRPKSs of known functions and showed that the PT domains can be classified into five groups, with each group corresponding to a unique product size or cyclization regioselectivity. Group V contains the formerly unverified PT domains that were identified as C6-C11 aldol cyclases. The regioselectivity of PTs from this group were verified by product-based assays using the PT domain excised from the asperthecin AptA NRPKS. When combined with dissociated PKS4 minimal PKS, or replaced the endogenous PKS4 C2-C7 PT domain in a hybrid NRPKS, AptA-PT directed the C6-C11 cyclization of the nonaketide backbone to yield a tetracyclic pyranoanthraquinone 4. Extensive NMR analysis verified that the backbone of 4 was indeed cyclized with the expected regioselectivity. The PT phylogenetic analysis was then expanded to include ϳ100 PT sequences from unverified NRPKSs. Using the assays developed for AptA-PT, the regioselectivities of additional PT domains were investigated and matched to those predicted by the phylogenetic classifications.

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confidence: 99%

“…Other representative products of NRPKSs include pigment precursors (1,3,6,THN), compounds with antibiotic (viridicatumtoxin) and anticancer (bikaverin) properties. Polyketides produced from NRPKSs are aromatic compounds with sizes ranging from monocyclic aromatics to those containing multiple fused rings.…”

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confidence: 99%

Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

Tang

2010

Journal of Biological Chemistry

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“…It is possible that one of the two cytochrome P 450 enzymes may catalyze more than one hydroxylation reaction, as previously found for the gibberellin biosynthesis. 19 Mass spectrometric based methods have been successfully used as powerful metabolite profiling tools for evaluating metabolic pathways. 20 The positive ion, high resolution electron spray ionization mass spectra, (HRESIMS) of 1- …”

Section: Resultsmentioning

confidence: 99%

Biosynthesis of aphidicolin proceeds via the mevalonate pathway in the endophytic fungus Nigrospora sphaerica

Lopes¹,

Pupo²

2011

J. Braz. Chem. Soc.

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Previamente o fungo endofítico Nigrospora sphaerica foi identificado como um profícuo produtor do diterpeno bioativo afidicolina. Neste artigo foi realizado um estudo a fim de se verificar as melhores condições para a produção do diterpeno em meio Czapek. A fonte de açúcar (glicose e sacarose) e o tempo de incubação (4-15 dias) foram otimizados, para posterior aplicação no estudo biossintético do diterpeno. Os níveis mais elevados da produção da afidicolina foram obtidos no 8° dia com 1% de glicose e no 12° dia com 3% de sacarose nos meios de cultura. A biossíntese da afidicolina foi estudada empregando [1- We have previously identified the endophytic fungus Nigrospora sphaerica as a prolific producer of the bioactive diterpene aphidicolin. Herein we report a study to establish the best conditions for the production of aphidicolin by N. sphaerica in Czapek medium. The sugar source (glucose and sucrose) and the incubation time (4-15 days) were optimized for further application on biosynthetic studies of the diterpene. The highest levels of production of aphidicolin were found on the 8 th day with 1%-glucose and on the 12 th day with 3%-sucrose based media. The biosynthesis of aphidicolin was investigated using [1- 13C]-D-glucose as a precursor, and showed that the isoprene units of aphidicolin are derived from the mevalonate pathway.

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“…Amatoxins, the deadly RNA transcription inhibitors produced by death angel mushrooms such as Amanita bisporigera, are produced by cleaving 35 amino acid proteins into octopeptides, which are then cyclized by a mechanism that is not fully understood (116). Polyketide synthetases, the most abundant SM-producing enzymes in fungi, polymerize fatty acid subunits rather than amino acid subunits like the nonribosomal peptide synthetases (115). A basic polyketide chain can be modified with functional group "decorations" and formed in rings by other enzymes in these pathways to produce a wide range of compounds.…”

Section: Major Types Of Secondary Metabolitesmentioning

confidence: 99%

“…Peptide SMs are usually synthesized by special polymerizing enzymes called nonribosomal peptide synthetases but are occasionally produced from repetitive DNA templates by cleavage of the resulting polypeptide sequences. Examples of nonribosomal peptide synthetase-produced SMs include the beta-lactam antibiotics such as penicillin and cephalosporin and the immunosuppressant cyclosporin (115). Amatoxins, the deadly RNA transcription inhibitors produced by death angel mushrooms such as Amanita bisporigera, are produced by cleaving 35 amino acid proteins into octopeptides, which are then cyclized by a mechanism that is not fully understood (116).…”

Section: Major Types Of Secondary Metabolitesmentioning

confidence: 99%

Six Key Traits of Fungi: Their Evolutionary Origins and Genetic Bases

et al. 2017

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The fungal lineage is one of the three large eukaryotic lineages that dominate terrestrial ecosystems. They share a common ancestor with animals in the eukaryotic supergroup Opisthokonta and have a deeper common ancestry with plants, yet several phenotypes, such as morphological, physiological, or nutritional traits, make them unique among all living organisms. This article provides an overview of some of the most important fungal traits, how they evolve, and what major genes and gene families contribute to their development. The traits highlighted here represent just a sample of the characteristics that have evolved in fungi, including polarized multicellular growth, fruiting body development, dimorphism, secondary metabolism, wood decay, and mycorrhizae. However, a great number of other important traits also underlie the evolution of the taxonomically and phenotypically hyperdiverse fungal kingdom, which could fill up a volume on its own. After reviewing the evolution of these six well-studied traits in fungi, we discuss how the recurrent evolution of phenotypic similarity, that is, convergent evolution in the broad sense, has shaped their phylogenetic distribution in extant species.

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Natural products of filamentous fungi: enzymes, genes, and their regulation

Cited by 500 publications

References 280 publications

Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

Biosynthesis of aphidicolin proceeds via the mevalonate pathway in the endophytic fungus Nigrospora sphaerica

Six Key Traits of Fungi: Their Evolutionary Origins and Genetic Bases

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