Previous studies showed that the Fe II /a-ketoglutarate dependent dioxygenase AsqJ induces askeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans,g enerating aq uinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates.Wereport that AsqJ catalyzesanadditional, entirely different reaction, simply by ac hange in substituent in the benzodiazepinedione substrate.This new mechanism is established by substrate screening,application of functional probes, and computational analysis.A sqJ excises H 2 CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5dione substrates to generate quinazolinones.T his novel AsqJ catalysis pathwayisgoverned by asingle substituent within the complex substrate.This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones,t wo alkaloid frameworks of exceptional biomedical relevance.
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.
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.
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