The terrestrial cyanobacterium Fischerella ambigua 108b produces the three polychlorinated triphenyls ambigol A–C that exhibit interesting antimicrobial, antiviral and cytotoxic activities. They are structurally related to polybrominated diphenylethers synthesized by...

What is the most significant result of this study?Many potent glycopeptide antibiotics, such as vancomycin, contain biaryl structural features. These are biosynthetically introduced by dedicated cytochrome P450 enzymes, which require their substrate to be bound to a carrier protein as a precondition for substrate recognition. AryC, by contrast, accepts free, untethered substrates to install the biaryl bond in arylomycin antibiotics. It is thus a unique enzyme for biaryl peptide construction with huge potential for the streamlined chemo-enzymatic synthesis of peptide antibiotics.

The arylomycin antibiotics are potent inhibitors of bacterial type I signal peptidase. These lipohexapeptides contain a biaryl structural motif reminiscent of glycopeptide antibiotics. We herein describe the functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly. Unlike its enzymatic counterparts in glycopeptide biosynthesis, AryC converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. This activity enables chemo‐enzymatic assembly of arylomycin A2 that combines the advantages of liquid‐ and solid‐phase peptide synthesis with late‐stage enzymatic cross‐coupling. The reactivity of AryC is unprecedented in cytochrome P450‐mediated biaryl construction in non‐ribosomal peptides, in which peptidyl carrier protein (PCP)‐tethering so far was shown crucial both in vivo and in vitro.

Sorbicillinoids are fungal polyketides characterized by highly complex and diverse molecular structures, with considerable stereochemical intricacy combined with a high degree of oxygenation. Many sorbicillinoids possess promising biological activities. An interesting member of this natural product family is sorbicatechol A, which is reported to have antiviral activity, particularly against influenza A virus (H1N1). Through a straightforward, one‐pot chemoenzymatic approach with recently developed oxidoreductase SorbC, the characteristic bicyclo[2.2.2]octane core of sorbicatechol is structurally diversified by variation of its natural 2‐methoxyphenol substituent. This facilitates the preparation of a focused library of structural analogues bearing substituted aromatic systems, alkanes, heterocycles, and ethers. Fast access to this structural diversity provides an opportunity to explore the antiviral potential of the sorbicatechol family.

The first total synthesis of all members of the cyanobacterial natural product class of the ambigols is described. Key steps of the synthetic strategy are the formation of sterically demanding mono- and bis-iodonium salts to install the required biaryl ether structural elements and Suzuki cross-coupling giving straightforward access to the biaryl bonds. The synthetic methods are also utilized to construct unnatural or hypothetical ambigols that are still awaiting discovery from Nature.

Enzymatic oxidative dearomatization is an efficient way to generate chiral molecules from simple arenes. One example is the flavindependent monooxygenase SorbC involved in sorbicillinoid biosynthesis. However, SorbC requires a long-chain keto substituent at its phenolic substrate, thus preventing its application beyond the synthesis of natural sorbicillinoids or close structural analogues. This work describes an approach to broaden the accessible product spectrum of SorbC by employing an ester functionality mimicking the natural substrate structure during enzymatic oxidation.

The cyanobacterium Fischerella ambigua is a natural producer of polychlorinated aromatic compounds, the ambigols A-E. The biosynthetic gene cluster (BGC) of these highly halogenated triphenyls has been recently identified by...

Most antibiotics in clinical use are inspired by natural products. Prominent examples are the glycopeptides, such as vancomycin. These compounds contain biaryl-and biaryl-ether bonds that are crucial for biological activity and biosynthetically get installed by dedicated cytochrome P450 enzymes. The application of these biocatalysts in the chemo-enzymatic synthesis of novel glycopeptides has been impeded by their strict requirement for peptidyl carrier-protein (PCP) bound substrates and additional X domain interactions. This necessitates equimolar amounts of protein tethers, precluding truly catalytic applications. We describe the functional and structural evaluation of AryC, the cytochrome P450 performing biaryl coupling in biosynthetic arylomycin assembly, and its application in the chemo-enzymatic synthesis of arylomycin A2. AryC efficiently converts free substrates without the requirement of any protein interaction partner, likely enabled by a strongly hydrophobic cavity at the surface of AryC pointing to the substrate tunnel. The resulting reactivity of AryC is unprecedented in cytochrome P450-mediated biaryl construction in non-ribosomal peptides, in which PCP-tethering so far was crucial both in vivo and in vitro. Our work thus provides a basis for the development of general biocatalytic platforms for the efficient biocatalytic synthesis of biaryl peptide antibiotics.