TY - JOUR
T1 - In Vitro Reconstitution of OxyC Activity Enables Total Chemoenzymatic Syntheses of Vancomycin Aglycone Variants
AU - Forneris, Clarissa C.
AU - Seyedsayamdost, Mohammad R.
N1 - Funding Information:
We thank Prof. E. J. Sorensen, Seyma Ozturk, and Prof. J. Clardy for helpful discussions and the National Institutes of Health (DP2-AI-124786 to M.R.S.), the Burroughs Wellcome Fund, and the Searle Scholars Program for support of this work. C.C.F. was generously supported by the Eli Lilly-Edward C. Taylor Fellowship in Chemistry.
Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/7/2
Y1 - 2018/7/2
N2 - The bioactivity of vancomycin is enabled by three aromatic crosslinks, the biosynthesis of which has been an active area of investigation for two decades. Two cytochrome P450 enzymes, OxyB and OxyA, have been shown to introduce bisaryl ether linkages with the help of a so-called X-domain. The final crosslink, however, a biaryl bond thought to be installed by OxyC, has remained elusive. We report the in vitro reconstitution of the OxyC reaction and formation of the first carbon–carbon crosslink in any glycopeptide antibiotic. Using a cascade sequence, in which the peptide substrate was incubated with the Oxy enzymes in turn, we completed the chemoenzymatic synthesis of a vancomycin aglycone variant. This approach was also used to generate a new analogue carrying a thioamide linkage at residue 4, a precursor to the amidine derivative, which is effective against vancomycin-resistant pathogens. Our results set the stage for creating therapeutic vancomycin derivatives by using the native metalloenzymes.
AB - The bioactivity of vancomycin is enabled by three aromatic crosslinks, the biosynthesis of which has been an active area of investigation for two decades. Two cytochrome P450 enzymes, OxyB and OxyA, have been shown to introduce bisaryl ether linkages with the help of a so-called X-domain. The final crosslink, however, a biaryl bond thought to be installed by OxyC, has remained elusive. We report the in vitro reconstitution of the OxyC reaction and formation of the first carbon–carbon crosslink in any glycopeptide antibiotic. Using a cascade sequence, in which the peptide substrate was incubated with the Oxy enzymes in turn, we completed the chemoenzymatic synthesis of a vancomycin aglycone variant. This approach was also used to generate a new analogue carrying a thioamide linkage at residue 4, a precursor to the amidine derivative, which is effective against vancomycin-resistant pathogens. Our results set the stage for creating therapeutic vancomycin derivatives by using the native metalloenzymes.
KW - OxyC
KW - antibiotics
KW - biosynthesis
KW - cytochrome P450 enzymes
KW - vancomycin
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U2 - 10.1002/anie.201802856
DO - 10.1002/anie.201802856
M3 - Article
C2 - 29697176
AN - SCOPUS:85049015486
SN - 1433-7851
VL - 57
SP - 8048
EP - 8052
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 27
ER -