Details
| Original language | English |
|---|---|
| Pages (from-to) | 20560-20565 |
| Number of pages | 6 |
| Journal | Journal of the American Chemical Society |
| Volume | 142 |
| Issue number | 49 |
| Early online date | 28 Nov 2020 |
| Publication status | Published - 9 Dec 2020 |
| Externally published | Yes |
Abstract
Bottromycins are ribosomally synthesized and post-translationally modified peptide natural product antibiotics that are effective against high-priority human pathogens such as methicillin-resistant Staphylococcus aureus. The total synthesis of bottromycins involves at least 17 steps, with a poor overall yield. Here, we report the characterization of the cytochrome P450 enzyme BotCYP from a bottromycin biosynthetic gene cluster. We determined the structure of a close BotCYP homolog and used our data to conduct the first large-scale survey of P450 enzymes associated with RiPP biosynthetic gene clusters. We demonstrate that BotCYP converts a C-terminal thiazoline to a thiazole via an oxidative decarboxylation reaction and provides stereochemical resolution for the pathway. Our data enable the two-pot in vitro production of the bottromycin core scaffold and may allow the rapid generation of bottromycin analogues for compound development.
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- General Chemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Chemical Engineering(all)
- Colloid and Surface Chemistry
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In: Journal of the American Chemical Society, Vol. 142, No. 49, 09.12.2020, p. 20560-20565.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Characterization of the Stereoselective P450 Enzyme BotCYP Enables the in Vitro Biosynthesis of the Bottromycin Core Scaffold
AU - Adam, Sebastian
AU - Franz, Laura
AU - Milhim, Mohammed
AU - Bernhardt, Rita
AU - Kalinina, Olga V.
AU - Koehnke, Jesko
N1 - Funding Information: J.K. thanks the German Research Foundation for an Emmy Noether Fellowship (KO 4116/3-2).
PY - 2020/12/9
Y1 - 2020/12/9
N2 - Bottromycins are ribosomally synthesized and post-translationally modified peptide natural product antibiotics that are effective against high-priority human pathogens such as methicillin-resistant Staphylococcus aureus. The total synthesis of bottromycins involves at least 17 steps, with a poor overall yield. Here, we report the characterization of the cytochrome P450 enzyme BotCYP from a bottromycin biosynthetic gene cluster. We determined the structure of a close BotCYP homolog and used our data to conduct the first large-scale survey of P450 enzymes associated with RiPP biosynthetic gene clusters. We demonstrate that BotCYP converts a C-terminal thiazoline to a thiazole via an oxidative decarboxylation reaction and provides stereochemical resolution for the pathway. Our data enable the two-pot in vitro production of the bottromycin core scaffold and may allow the rapid generation of bottromycin analogues for compound development.
AB - Bottromycins are ribosomally synthesized and post-translationally modified peptide natural product antibiotics that are effective against high-priority human pathogens such as methicillin-resistant Staphylococcus aureus. The total synthesis of bottromycins involves at least 17 steps, with a poor overall yield. Here, we report the characterization of the cytochrome P450 enzyme BotCYP from a bottromycin biosynthetic gene cluster. We determined the structure of a close BotCYP homolog and used our data to conduct the first large-scale survey of P450 enzymes associated with RiPP biosynthetic gene clusters. We demonstrate that BotCYP converts a C-terminal thiazoline to a thiazole via an oxidative decarboxylation reaction and provides stereochemical resolution for the pathway. Our data enable the two-pot in vitro production of the bottromycin core scaffold and may allow the rapid generation of bottromycin analogues for compound development.
UR - http://www.scopus.com/inward/record.url?scp=85097581106&partnerID=8YFLogxK
U2 - 10.1021/jacs.0c10361
DO - 10.1021/jacs.0c10361
M3 - Article
C2 - 33249843
AN - SCOPUS:85097581106
VL - 142
SP - 20560
EP - 20565
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 49
ER -