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Carrier Protein‐Free Enzymatic Biaryl Coupling in Arylomycin A2 Assembly and Structure of the Cytochrome P450 AryC **
Author(s) -
Aldemir Hülya,
Shu Shuangjie,
Schaefers Francoise,
Hong Hanna,
Richarz René,
Harteis Sabrina,
Einsiedler Manuel,
Milzarek Tobias M.,
Schneider Sabine,
Gulder Tobias A. M.
Publication year - 2022
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202103389
Subject(s) - enzyme , cytochrome p450 , chemistry , biochemistry , cytochrome , glycopeptide , peptide , stereochemistry , combinatorial chemistry , 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.