Installation of multiple aryl ether crosslinks onto non-native substrate peptides by the vancomycin OxyB

TETRAHEDRON

卷:74

Article; Proceedings Paper

Forneris, Clarissa C.¹  Ozturk, Seyma¹  Sorensen, Erik J.¹  Seyedsayamdost, Mohammad R.^1,2 

[1] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA

[2] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA

关键词: Natural products;    Biosynthesis;    Vancomycin;    Metalloenzyme;   

DOI  :  10.1016/j.tet.2018.04.028

来源: Elsevier

【 摘 要 】

The biosynthesis of glycopeptide antibiotics (GPAs) has been an active area of research for decades. But, insights into the activity of the cytochrome P450 enzymes required for installing the aromatic crosslinks, which form their cup-shaped topologies and render GPAs bioactive, have only recently emerged. Presently, little is known about the substrate scope and promiscuity of the P450 enzymes. Herein, we report that OxyBvan, the P450 enzyme that installs the first crosslink in vancomycin biosynthesis, is capable of catalyzing the formation of its conventional C-O-D bis-aryl ether bond in non-natural substrates and, furthermore, the formation of a second, novel linkage when D-Trp is incorporated at position 6. HR-MS/MS and isotope labeling studies indicate the second crosslink is formed between rings A and B, resulting in a novel CPA-type scaffold. OxyB is also capable of installing two crosslinks in kistamicin- and complestatin-like substrate peptides. These findings highlight the utility of OxyBvan in creating cross linked GPA derivatives and provide clues regarding the unusual biosynthesis of kistamicin. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

Free