Asperphenamate biosynthesis reveals a novel two-module NRPS system to synthesize amino acid esters in fungi

Li, Wei; Fan, Aili; Wang, Long; Zhang, Peng; Liu, Zhiguo; An, Zhiqiang; Yin, Wen

doi:10.1039/c7sc02396k

Cited by 31 publications

(31 citation statements)

References 28 publications

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“…Asperphenamate and its derivatives have been reported from the fungal genera Penicillium and Aspergillus with antimicrobial and anticancer activities [53,54]. These are rare linear amino acid esters derived from nonribosomal peptides [55]. Another parent ion identified in all three Penicillium strains was meroterpenoid mycophenolic acid, a polyketide-terpene hybrid composed of a phthalide moiety and a terpenoid side chain.…”

Section: Discussionmentioning

confidence: 99%

Mining the Metabolome and the Agricultural and Pharmaceutical Potential of Sea Foam-Derived Fungi

et al. 2020

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Sea foam harbors a diverse range of fungal spores with biological and ecological relevance in marine environments. Fungi are known as the producers of secondary metabolites that are used in health and agricultural sectors, however the potentials of sea foam-derived fungi have remained unexplored. In this study, organic extracts of six foam-derived fungal isolates belonging to the genera Penicillium, Cladosporium, Emericellopsis and Plectosphaerella were investigated for their antimicrobial activity against plant and human pathogens and anticancer activity. In parallel, an untargeted metabolomics study using UPLC-QToF–MS/MS-based molecular networking (MN) was performed to unlock their chemical inventory. Penicillium strains were identified as the most prolific producers of compounds with an average of 165 parent ions per strain. In total, 49 known mycotoxins and functional metabolites were annotated to specific and ubiquitous parent ions, revealing considerable chemical diversity. This allowed the identification of putative new derivatives, such as a new analog of the antimicrobial tetrapeptide, fungisporin. Regarding bioactivity, the Penicillium sp. isolate 31.68F1B showed a strong and broad-spectrum activity against seven plant and human pathogens, with the phytopathogen Magnaporthe oryzae and the human pathogen Candida albicans being the most susceptible (IC50 values 2.2 and 6.3 µg/mL, respectively). This is the first study mining the metabolome of the sea foam-derived fungi by MS/MS-based molecular networking, and assessing their biological activities against phytopathogens.

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Section: Discussionmentioning

confidence: 99%

Mining the Metabolome and the Agricultural and Pharmaceutical Potential of Sea Foam-Derived Fungi

et al. 2020

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“…Li et al 114 The R domain in ApmA releases Nbenzoylphenylalaninol, which acts as a nucleophile in the ester bond forming reaction in the C-terminal C domain of ApmB, releasing asperphenamate. Note that the famous compound taxol has a depsipeptide moiety that resembles asperphenamate, but taxol is synthesized by yew trees in a completely different manner 251 the next peptide intermediate (peptidyl n+1 -S-PCP), oligomerization occurs (peptidyl n -peptidyl n+1 -S-PCP).…”

Section: F I G U R E 8 Proposed Asperphenamate Biosynthesis Based Onmentioning

confidence: 99%

Biosynthesis of depsipeptides, or Depsi: The peptides with varied generations

Alonzo

Schmeing

2020

Protein Science

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Depsipeptides are compounds that contain both ester bonds and amide bonds. Important natural product depsipeptides include the piscicide antimycin, the K + ionophores cereulide and valinomycin, the anticancer agent cryptophycin, and the antimicrobial kutzneride. Furthermore, database searches return hundreds of uncharacterized systems likely to produce novel depsipeptides. These compounds are made by specialized nonribosomal peptide synthetases (NRPSs). NRPSs are biosynthetic megaenzymes that use a module architecture and multi-step catalytic cycle to assemble monomer substrates into peptides, or in the case of specialized depsipeptide synthetases, depsipeptides. Two NRPS domains, the condensation domain and the thioesterase domain, catalyze ester bond formation, and ester bonds are introduced into depsipeptides in several different ways. The two most common occur during cyclization, in a reaction between a hydroxy-containing side chain and the C-terminal amino acid residue in a peptide intermediate, and during incorporation into the growing peptide chain of an α-hydroxy acyl moiety, recruited either by direct selection of an α-hydroxy acid substrate or by selection of an α-keto acid substrate that is reduced in situ. In this article, we discuss how and when these esters are introduced during depsipeptide synthesis, survey notable depsipeptide synthetases, and review insight into bacterial depsipeptide synthetases recently gained from structural studies.

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“…Likewise, through heterologous expression in A. nidulans, the synthesis of asperphenamate has been demonstrated to be dependent on the joint action of two distinct NRPSs: ApmA and ApmB. Indeed, the NRP produced by ApmA, N-benzoylphenylalaninol, binds onto the monomer attached to ApmB to generate subsequently the asperphenamate compound (Li et al, 2018). On the other hand, there are some studies reporting identification and confirmation of NRP biosynthetic pathways through heterologous expression.…”

Section: Filamentous Fungi Heterologous Expression Systemsmentioning

confidence: 99%

“…In another filamentous fungus, A. nidulans, asperphenamate production was knocked down by mutating the apmA gene responsible for N-benzoylphenylalaninol biosynthesis. This production was subsequently restored by feeding the same strain with the deficient precursor (Li et al, 2018). In yeast, the relevance of precursor supplementation in the culture medium has been highlighted in H. polymorpha expressing pcbAB NRPS gene.…”

Section: How To Address Nrp Precursors Deficiency?mentioning

confidence: 99%

Nonribosomal peptides in fungal cell factories: from genome mining to optimized heterologous production

Vassaux

Meunier

Vandenbol

et al. 2019

Biotechnology Advances

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Asperphenamate biosynthesis reveals a novel two-module NRPS system to synthesize amino acid esters in fungi

Abstract: Characterisation of asperphenamate biosynthetic pathway in Penicillium brevicompactum reveals a novel two modular NRPS system for the formation of amino acid esters in nature.

Cited by 31 publications

References 28 publications

Mining the Metabolome and the Agricultural and Pharmaceutical Potential of Sea Foam-Derived Fungi

Mining the Metabolome and the Agricultural and Pharmaceutical Potential of Sea Foam-Derived Fungi

Biosynthesis of depsipeptides, or Depsi: The peptides with varied generations

Nonribosomal peptides in fungal cell factories: from genome mining to optimized heterologous production

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