Installation of Multiple Aryl Ether Crosslinks onto Non-Native Substrate Peptides by the Vancomycin OxyB.

TitleInstallation of Multiple Aryl Ether Crosslinks onto Non-Native Substrate Peptides by the Vancomycin OxyB.
Publication TypeJournal Article
Year of Publication2018
AuthorsForneris, CC, Ozturk, S, Sorensen, EJ, Seyedsayamdost, MR
JournalTetrahedron
Volume74
Issue26
Pagination3231-3237
Date Published2018 Jun 28
ISSN0040-4020
Abstract

The biosynthesis of glycopeptide antibiotics (GPAs) has been an active area of research for decades. Nonetheless, 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 OxyB, the P450 enzyme that installs the first crosslink in vancomycin biosynthesis, is capable of catalyzing the formation of its conventional C--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 GPA-type scaffold. OxyB is also capable of installing two crosslinks in kistamicin- and complestatin-like substrate peptides. These findings highlight the utility of OxyB in creating crosslinked GPA derivatives and provide clues regarding the unusual biosynthesis of kistamicin.

DOI10.1016/j.tet.2018.04.028
Alternate JournalTetrahedron
PubMed ID30386000
PubMed Central IDPMC6205514
Grant ListDP2 AI124786 / AI / NIAID NIH HHS / United States
R01 GM065483 / GM / NIGMS NIH HHS / United States