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

Clarissa C. Forneris, Seyma Ozturk, Erik J. Sorensen, Mohammad R. Seyedsayamdost

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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 GPA-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 crosslinked GPA derivatives and provide clues regarding the unusual biosynthesis of kistamicin.

Original languageEnglish (US)
Pages (from-to)3231-3237
Number of pages7
JournalTetrahedron
Volume74
Issue number26
DOIs
StatePublished - Jun 28 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Biosynthesis
  • Metalloenzyme
  • Natural products
  • Vancomycin

Fingerprint Dive into the research topics of 'Installation of multiple aryl ether crosslinks onto non-native substrate peptides by the vancomycin OxyB'. Together they form a unique fingerprint.

  • Cite this