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Characterization of the Stereoselective P450 Enzyme BotCYP Enables the Biosynthesis of the Bottromycin Core Scaffold.
Franz, Laura Milhim, Mohammed Bernhardt, Rita Kalinina, Olga V Koehnke, Jesko
Franz, Laura
Milhim, Mohammed
Bernhardt, Rita
Kalinina, Olga V
Koehnke, Jesko
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2020-11-28
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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.
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J Am Chem Soc. 2020 Dec 9;142(49):20560-20565. doi: 10.1021/jacs.0c10361. Epub 2020 Nov 28.
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en
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1520-5126
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Attribution 4.0 International