Abstract
Kistamicin is a divergent member of the glycopeptide antibiotics, a structurally complex class of important, clinically relevant antibiotics often used as the last resort against resistant bacteria. The extensively crosslinked structure of these antibiotics that is essential for their activity makes their chemical synthesis highly challenging and limits their production to bacterial fermentation. Kistamicin contains three crosslinks, including an unusual 15-membered A-O-B ring, despite the presence of only two Cytochrome P450 Oxy enzymes thought to catalyse formation of such crosslinks within the biosynthetic gene cluster. In this study, we characterise the kistamicin cyclisation pathway, showing that the two Oxy enzymes are responsible for these crosslinks within kistamicin and that they function through interactions with the X-domain, unique to glycopeptide antibiotic biosynthesis. We also show that the kistamicin OxyC enzyme is a promiscuous biocatalyst, able to install multiple crosslinks into peptides containing phenolic amino acids.
| Original language | English |
|---|---|
| Article number | 2613 |
| Number of pages | 15 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 13 Jun 2019 |
Keywords
- biosynthesis
- enzyme mechanisms
- x-ray crystallography
Cite this
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Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics. / Greule, Anja; Izoré, Thierry; Iftime, Dumitrita; Tailhades, Julien; Schoppet, Melanie; Zhao, Yongwei; Peschke, Madeleine; Ahmed, Iftekhar; Kulik, Andreas; Adamek, Martina; Goode, Robert J.A.; Schittenhelm, Ralf B.; Kaczmarski, Joe A.; Jackson, Colin J.; Ziemert, Nadine; Krenske, Elizabeth H.; De Voss, James J.; Stegmann, Evi; Cryle, Max J.
In: Nature Communications, Vol. 10, No. 1, 2613, 13.06.2019.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Kistamicin biosynthesis reveals the biosynthetic requirements for production of highly crosslinked glycopeptide antibiotics
AU - Greule, Anja
AU - Izoré, Thierry
AU - Iftime, Dumitrita
AU - Tailhades, Julien
AU - Schoppet, Melanie
AU - Zhao, Yongwei
AU - Peschke, Madeleine
AU - Ahmed, Iftekhar
AU - Kulik, Andreas
AU - Adamek, Martina
AU - Goode, Robert J.A.
AU - Schittenhelm, Ralf B.
AU - Kaczmarski, Joe A.
AU - Jackson, Colin J.
AU - Ziemert, Nadine
AU - Krenske, Elizabeth H.
AU - De Voss, James J.
AU - Stegmann, Evi
AU - Cryle, Max J.
PY - 2019/6/13
Y1 - 2019/6/13
N2 - Kistamicin is a divergent member of the glycopeptide antibiotics, a structurally complex class of important, clinically relevant antibiotics often used as the last resort against resistant bacteria. The extensively crosslinked structure of these antibiotics that is essential for their activity makes their chemical synthesis highly challenging and limits their production to bacterial fermentation. Kistamicin contains three crosslinks, including an unusual 15-membered A-O-B ring, despite the presence of only two Cytochrome P450 Oxy enzymes thought to catalyse formation of such crosslinks within the biosynthetic gene cluster. In this study, we characterise the kistamicin cyclisation pathway, showing that the two Oxy enzymes are responsible for these crosslinks within kistamicin and that they function through interactions with the X-domain, unique to glycopeptide antibiotic biosynthesis. We also show that the kistamicin OxyC enzyme is a promiscuous biocatalyst, able to install multiple crosslinks into peptides containing phenolic amino acids.
AB - Kistamicin is a divergent member of the glycopeptide antibiotics, a structurally complex class of important, clinically relevant antibiotics often used as the last resort against resistant bacteria. The extensively crosslinked structure of these antibiotics that is essential for their activity makes their chemical synthesis highly challenging and limits their production to bacterial fermentation. Kistamicin contains three crosslinks, including an unusual 15-membered A-O-B ring, despite the presence of only two Cytochrome P450 Oxy enzymes thought to catalyse formation of such crosslinks within the biosynthetic gene cluster. In this study, we characterise the kistamicin cyclisation pathway, showing that the two Oxy enzymes are responsible for these crosslinks within kistamicin and that they function through interactions with the X-domain, unique to glycopeptide antibiotic biosynthesis. We also show that the kistamicin OxyC enzyme is a promiscuous biocatalyst, able to install multiple crosslinks into peptides containing phenolic amino acids.
KW - biosynthesis
KW - enzyme mechanisms
KW - x-ray crystallography
UR - http://www.scopus.com/inward/record.url?scp=85067369782&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10384-w
DO - 10.1038/s41467-019-10384-w
M3 - Article
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2613
ER -