Enantioselective Phenol Coupling by Laccases in the Biosynthesis of Fungal Dimeric Naphthopyrones

Obermaier, Sebastian; Thiele, Wiebke; Fürtges, Leon; Müller, Michael

doi:10.1002/ange.201903759

Cited by 14 publications

(9 citation statements)

References 27 publications

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“…The A. aculeatus bfoB strain yielded nigerone (2a) and bifonsecin B (2b); the A. aculeatus aunB strain yielded aurasperone A (3a) and aurasperone B (3b). For the other monomeric substances, fonsecin (5) and flavasperone (6), no formation of dimers was detected.…”

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confidence: 91%

Biaryl-Forming Enzymes from Aspergilli Exhibit Substrate-Dependent Stereoselectivity

Obermaier

Müller

2019

Biochemistry

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Natural biaryls typically occur as one regio- and atropisomeric variant in a given organism. Here, we report on the identification of biosynthetic genes of aurasperone- and bifonsecin-type biaryls in several Aspergillus species. The genes of the tailoring enzymes form a gene cluster that is separate from the polyketide synthase gene. Dimerization of naphthopyrone monomers is catalyzed by members of an undescribed subfamily of cytochrome P450 enzymes. The stereoselectivity of these enzymes is influenced by the two natural monomeric substrates; homodimerization of one monomer yields a stereochemically pure biaryl, while the other monomer yields a mixture of enantiomers.

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confidence: 91%

Biaryl-Forming Enzymes from Aspergilli Exhibit Substrate-Dependent Stereoselectivity

Obermaier

Müller

2019

Biochemistry

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“…The bis-naphthopyrone-type pigments are widely produced by different fungi that can protect filamentous fungi from fungivores [ 62 ] or abiotic stress factors like UV radiation and high temperatures [ 63 , 64 ]. Genome survey indicated that both C. militaris and C. cicadae contain a conserved PKS BGC like that of rice false smut Ustilaginoidea virens ( Figure 3 D), which is responsible for the production of ustilaginoidins [ 65 ]. Different analogs of ustilaginoidins have varied level of antibacterial, cytotoxic, and phytotoxic activities [ 66 ].…”

Section: Unknown Mycotoxins May Be Produced By Cordycepsmentioning

confidence: 99%

Bioactive Metabolites and Potential Mycotoxins Produced by Cordyceps Fungi: A Review of Safety

Chen

Sun

Luo

et al. 2020

Toxins

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Ascomycete Cordyceps fungi such as C. militaris, C. cicadae, and C. guangdongensis have been mass produced on artificial media either as food supplements or health additives while the byproducts of culture substrates are largely used as animal feed. The safety concerns associated with the daily consumption of Cordyceps fungi or related products are still being debated. On the one hand, the known compounds from these fungi such as adenosine analogs cordycepin and pentostatin have demonstrated different beneficial or pharmaceutical activities but also dose-dependent cytotoxicities, neurological toxicities and or toxicological effects in humans and animals. On the other hand, the possibility of mycotoxin production by Cordyceps fungi has not been completely ruled out. In contrast to a few metabolites identified, an array of biosynthetic gene clusters (BGCs) are encoded in each genome of these fungi with the potential to produce a plethora of as yet unknown secondary metabolites. Conservation analysis of BGCs suggests that mycotoxin analogs of PR-toxin and trichothecenes might be produced by Cordyceps fungi. Future elucidation of the compounds produced by these functionally unknown BGCs, and in-depth assessments of metabolite bioactivity and chemical safety, will not only facilitate the safe use of Cordyceps fungi as human food or alternative medicine, but will also benefit the use of mass production byproducts as animal feed. To corroborate the long record of use as a traditional medicine, future efforts will also benefit the exploration of Cordyceps fungi for pharmaceutical purposes.

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“…Nature has evolved catalysts for oxidative dimerization of phenolic compounds to generate biaryl natural products. 53,54 Whereas a growing number of these catalysts have been identified in biosynthetic pathways of biaryl natural products (Supplemental Table S2), [55][56][57][58][59][60][61][62][63][64][65][66][67][68] a much more vast pool of related sequences remains underexplored with untapped potential to catalyze a diverse array of oxidative coupling reactions (see sequence similarity network, SSN, in Figure 1d). Both laccases and cytochrome P450 monooxygenases (P450s) are known to carry out this transformation.…”

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“…Both laccases and cytochrome P450 monooxygenases (P450s) are known to carry out this transformation. 9 Although laccases have been employed in biocatalysis, these enzymes have only been shown to exert control over the selectivity of the C-C bond-forming event following the initial oxidation in a limited number of examples, 68,69 as laccases more commonly afford complex product mixtures. 70,71 In contrast, P450s associated with secondary metabolite biosynthesis often exhibit excellent control over the site-and atroposelectivity in oxidative coupling reactions.…”

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Biaryl bond formation through biocatalytic oxidative cross-coupling reactions

Zetzsche

Yazarians

Chakrabarty

et al. 2021

Preprint

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Biocatalysis offers compelling advantages in synthesis, often becoming the method of choice based on sustainability, safety, and selectivity considerations. Despite these advantages, enzymes in synthesis are typically dedicated to functional group intercon versions in linear synthetic sequences and have not been broadly integrated into the retrosynthetic logic for carbon skeleton assembly. In this article, we disclose a biocatalytic platform for fragment coupling to assemble target molecules convergently. Specifically, we report a strategy for biocatalytic phenolic cross-coupling through oxidative C-C bond formation. Using cytochrome P450 enzymes, we demonstrate the ability to catalyze cross-coupling reactions on a panel of phenolic substrates and further demonstrate the ability to tune these catalysts to possess the desired reactivity, site-, and atroposelectivity. This streamlined method for constructing sterically-hindered biaryl bonds provides an engineerable platform for assembling molecules with programmable catalyst-controlled reactivity and selectivity unprecedented with small molecule catalysts.Convergent synthetic strategies enable the efficient construction of carbon frameworks, quickly generating complexity by stitching individual building blocks together. 1 Chemists depend on transformations, such as cross-coupling reactions, that can reliably be programmed into synthetic routes for convergent approaches. 2 Ideally, reactions planned for the assembly phase of a convergent synthesis are both perfectly selective and tolerate a breadth of functional groups to minimize the production of undesired products, installation of protecting groups, or unnecessary redox manipulations. 3 These qualities are common in biocatalytic reactions due to the catalyst-controlled selectivity possible with large molecule catalysts; 4 however, the enzymatic transformations most commonly applied in synthesis are confined to functional group interconversions, not convergent steps within a synthetic route. [5][6][7][8][9][10][11] To enable convergent biocatalytic strategies, a handful of biocatalytic methods have recently been developed, [12][13][14][15] foreshadowing the potential of convergent biocatalysis in synthesis. Based on the paucity of enzyme-mediated methods for uniting substantial fragments, we developed an intense interest in expanding the repertoire of biocatalysts capable of convergent fragment couplings. As a first step toward this goal, we sought to develop a platform for the biocatalytic assembly of carbon frameworks through oxidative cross-coupling reactions, thus providing a solution for this transformation's outstanding reactivity and selectivity challenges through biocatalysis and enabling convergent synthetic routes (Figure 1a).We chose to target biaryl bond formation as a model transformation for convergent cross-coupling reactions, given the ubiquitous nature of biaryl scaffolds in drugs, materials, and ligands for asymmetric catalysis (Figure 1b) and the fundamental synthetic challenges presented by the...

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Enantioselective Phenol Coupling by Laccases in the Biosynthesis of Fungal Dimeric Naphthopyrones

Cited by 14 publications

References 27 publications

Biaryl-Forming Enzymes from Aspergilli Exhibit Substrate-Dependent Stereoselectivity

Biaryl-Forming Enzymes from Aspergilli Exhibit Substrate-Dependent Stereoselectivity

Bioactive Metabolites and Potential Mycotoxins Produced by Cordyceps Fungi: A Review of Safety

Biaryl bond formation through biocatalytic oxidative cross-coupling reactions

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