Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Chiang, Chen‐Yu; Ohashi, M.; Tang, Yi

doi:10.1039/d2np00050d

Cited by 39 publications

(35 citation statements)

References 207 publications

(302 reference statements)

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“…Also, recent developments in the biochemical techniques present fascinating possibilities to researchers. Aer the sequencing of many genomes and the establishment of methods to rapidly gain access to recombinant biosynthetic enzymes through genome mining, 181 isotopically labelled compounds can be used in vitro to study enzymatic reactions including their mechanisms. Another important and frequently used strategy makes use of heterologous gene expression, e.g., in Escherichia coli, Saccharomyces cerevisiae and Aspergillus oryzae.…”

Section: Acyclic Scaffoldsmentioning

confidence: 99%

“…Another important and frequently used strategy makes use of heterologous gene expression, e.g., in Escherichia coli, Saccharomyces cerevisiae and Aspergillus oryzae. 181,182 Retrospectively, it seems that with the upcoming possibilities of biochemical methods, isotopic labelling experiments have been pushed into the background, but they have certainly experienced a revival and will continue to be of enormous importance for biosynthetic research in the future.…”

Section: Acyclic Scaffoldsmentioning

confidence: 99%

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Labelling studies in the biosynthesis of polyketides and non-ribosomal peptides

Hou

Dickschat

2023

Nat. Prod. Rep.

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Section: Acyclic Scaffoldsmentioning

confidence: 99%

Section: Acyclic Scaffoldsmentioning

confidence: 99%

Labelling studies in the biosynthesis of polyketides and non-ribosomal peptides

Hou

Dickschat

2023

Nat. Prod. Rep.

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“…Obviously, the highly active functional groups including epoxide, cyclopropane, aziridine, and imine in their chemical structures play an important role in alkylating DNA to form the DNA–drug adduct. Elucidation of their biosynthetic pathways not only facilitates the discovery of new NPs with these biological active groups by genome mining but also is valuable for engineering NPs and drug design [ 147 ]. The unprecedented enzymology involved in their biosynthetic pathways can exert a positive influence on the development of biocatalysts as well.…”

Section: Perspectivementioning

confidence: 99%

Biosynthesis of DNA-Alkylating Antitumor Natural Products

Nie

Hou

et al. 2022

Molecules

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DNA-alkylating natural products play an important role in drug development due to their significant antitumor activities. They usually show high affinity with DNA through different mechanisms with the aid of their unique scaffold and highly active functional groups. Therefore, the biosynthesis of these natural products has been extensively studied, especially the construction of their pharmacophores. Meanwhile, their producing strains have evolved corresponding self-resistance strategies to protect themselves. To further promote the functional characterization of their biosynthetic pathways and lay the foundation for the discovery and rational design of DNA alkylating agents, we summarize herein the progress of research into DNA-alkylating antitumor natural products, including their biosynthesis, modes of action, and auto-resistance mechanisms.

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“…For fungal genes, there are several strains available, including S. cerevisiae and well-characterized Aspergillus sp. [25]. To achieves efficient biopreparation of OA and its derivatives, the filamentous fungus A. oryzae was selected as the heterologous expression host, which can synthesize polyketides, terpenoids, nonribosomal peptides, and their post-modification products [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

High-efficient production of mushroom polyketide compounds in a platform host Aspergillus oryzae

Han

Jing

et al. 2023

Microb Cell Fact

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Background Orsellinic acid (2,4-dihydroxy-6-methylbenzoic acid, OA) and its structural analog o-Orsellinaldehyde, have become widely used intermediates in clinical drugs synthesis. Although the research on the biosynthesis of such compounds has made significant progress, due to the lack of suitable hosts, there is still far from the industrial production of such compounds based on synthetic biology. Results With the help of genome mining, we found a polyketide synthase (PKS, HerA) in the genome of the Hericium erinaceus, which shares 60% amino acid sequence homology with ArmB from Armillaria mellea, an identified PKS capable of synthesizing OA. To characterize the function of HerA, we cloned herA and heterologously expressed it in Aspergillus oryzae, and successfully detected the production of OA. Subsequently, the introduction of an incomplete PKS (Pks5) from Ustilago maydis containing only three domains (AMP-ACP-R), which was into herA-containing A. oryzae, the resulted in the production of o-Orsellinaldehyde. Considering the economic value of OA and o-Orsellinaldehyde, we then optimized the yield of these compounds in A. oryzae. The screening showed that when maltose was used as carbon source, the yields of OA and o-Orsellinaldehyde were 57.68 mg/L and 15.71 mg/L respectively, while the yields were 340.41 mg/Kg and 84.79 mg/Kg respectively in rice medium for 10 days. Conclusions Herein, we successfully expressed the genes of basidiomycetes using A. oryzae heterologous host. As a fungus of ascomycetes, which not only correctly splices genes of basidiomycetes containing multiple introns, but also efficiently produces their metabolites. This study highlights that A. oryzae is an excellent host for the heterologous production of fungal natural products, and has the potential to become an efficient chassis for the production of basidiomycete secondary metabolites in synthetic biology. Graphical Abstract

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Deciphering chemical logic of fungal natural product biosynthesis through heterologous expression and genome mining

Abstract: Heterologous expression of biosynthetic gene clusters (BGCs) has become a widely used tool for genome mining of cryptic pathways, bottom-up investigation of biosynthetic enzymes, and engineered biosynthesis of new natural product variants.

Cited by 39 publications

References 207 publications

Labelling studies in the biosynthesis of polyketides and non-ribosomal peptides

Labelling studies in the biosynthesis of polyketides and non-ribosomal peptides

Biosynthesis of DNA-Alkylating Antitumor Natural Products

High-efficient production of mushroom polyketide compounds in a platform host Aspergillus oryzae

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