Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany.
Biosystems Chemistry, Faculty of Chemistry, Technical University of Munich, Lichtenbergstraße 4, 85748, Garching, Germany.
Chemistry. 2022 Jan 10;28(2):e202103389. doi: 10.1002/chem.202103389. Epub 2021 Nov 26.
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.
芳基霉素抗生素是细菌 I 型信号肽酶的有效抑制剂。这些脂六肽含有联苯结构基序，让人联想到糖肽抗生素。本文描述了芳基霉素生物合成中进行联苯偶联的细胞色素 P450 AryC 的功能和结构评估。与糖肽生物合成中的酶对应物不同，AryC 在没有任何蛋白质相互作用伙伴的情况下转化游离底物，这可能是由于 AryC 表面指向底物隧道的强疏水性腔所致。这种活性使芳基霉素 A2 的化学酶促组装成为可能，该组装结合了液相和固相肽合成以及后期酶交叉偶联的优势。在非核糖体肽中，细胞色素 P450 介导的联苯结构中，AryC 的反应性是前所未有的，迄今为止，在体内和体外都表明肽酰载体蛋白 (PCP) 连接对于该反应性至关重要。
