TY - JOUR
T1 - Installation of multiple aryl ether crosslinks onto non-native substrate peptides by the vancomycin OxyB
AU - Forneris, Clarissa C.
AU - Ozturk, Seyma
AU - Sorensen, Erik J.
AU - Seyedsayamdost, Mohammad R.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/6/28
Y1 - 2018/6/28
N2 - 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.
AB - 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.
KW - Biosynthesis
KW - Metalloenzyme
KW - Natural products
KW - Vancomycin
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U2 - 10.1016/j.tet.2018.04.028
DO - 10.1016/j.tet.2018.04.028
M3 - Article
C2 - 30386000
AN - SCOPUS:85046641717
SN - 0040-4020
VL - 74
SP - 3231
EP - 3237
JO - Tetrahedron
JF - Tetrahedron
IS - 26
ER -