Abstract
The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the halogenation of specific residues within the peptide. The timing of halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes.
| Original language | English |
|---|---|
| Pages (from-to) | 1239-1247 |
| Number of pages | 9 |
| Journal | Biochemistry |
| Volume | 56 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 7 Mar 2017 |
Cite this
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Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency. / Peschke, Madeleine; Brieke, Clara; Goode, Rob J. A.; Schittenhelm, Ralf B.; Cryle, Max J.
In: Biochemistry, Vol. 56, No. 9, 07.03.2017, p. 1239-1247.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Chlorinated Glycopeptide Antibiotic Peptide Precursors Improve Cytochrome P450-Catalyzed Cyclization Cascade Efficiency
AU - Peschke, Madeleine
AU - Brieke, Clara
AU - Goode, Rob J. A.
AU - Schittenhelm, Ralf B.
AU - Cryle, Max J.
PY - 2017/3/7
Y1 - 2017/3/7
N2 - The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the halogenation of specific residues within the peptide. The timing of halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes.
AB - The activity of glycopeptide antibiotics (GPAs) depends upon important structural modifications to their precursor heptapeptide backbone: specifically, the cytochrome P450-catalyzed oxidative cross-linking of aromatic side chains as well as the halogenation of specific residues within the peptide. The timing of halogenation and its effect on the cyclization of the peptide are currently unclear. Our results show that chlorination of peptide precursors improves their processing by P450 enzymes in vitro, which provides support for GPA halogenation occurring prior to peptide cyclization during nonribosomal peptide synthesis. We could also determine that the activity of the second enzyme in the oxidative cyclization cascade, OxyA, remains higher for chlorinated peptide substrates even when the biosynthetic GPA product possesses an altered chlorination pattern, which supports the role of the chlorine atoms in orienting the peptide substrate in the active site of these enzymes.
UR - http://www.scopus.com/inward/record.url?scp=85014722807&partnerID=8YFLogxK
U2 - 10.1021/acs.biochem.6b01102
DO - 10.1021/acs.biochem.6b01102
M3 - Article
AN - SCOPUS:85014722807
VL - 56
SP - 1239
EP - 1247
JO - Biochemistry
JF - Biochemistry
SN - 0006-2960
IS - 9
ER -