Mechanistic Studies of Aziridine Formation Catalyzed by Mononuclear Non-Heme Iron Enzymes
Aziridines are compounds with a nitrogen-containing three-membered ring. When it is incorporated into natural products, the reactivity of the strained ring often drives the biological activities of aziridines. Despite its importance, the enzymes and biosynthetic strategies deployed to install this reactive moiety remain understudied. Herein, we report the use of in silico methods to identify enzymes with potential aziridine-installing (aziridinase) functionality. To validate candidates, we reconstitute enzymatic activity in vitro and demonstrate that an iron(IV)-oxo species initiates aziridine ring closure by the C-H bond cleavage. Furthermore, we divert the reaction pathway from aziridination to hydroxylation using mechanistic probes. This observation, isotope tracing experiments using H218O and 18O2, and quantitative product analysis, provide evidence for the polar capture of a carbocation species by the amine in the pathway to aziridine installation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:145 |
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| Enthalten in: |
Journal of the American Chemical Society - 145(2023), 11 vom: 22. März, Seite 6240-6246 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cha, Lide [VerfasserIn] |
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| Links: |
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| Themen: |
54P5FEX9FH |
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| Anmerkungen: |
Date Completed 23.03.2023 Date Revised 31.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/jacs.2c12664 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM35419125X |
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| 500 | |a Date Revised 31.03.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Aziridines are compounds with a nitrogen-containing three-membered ring. When it is incorporated into natural products, the reactivity of the strained ring often drives the biological activities of aziridines. Despite its importance, the enzymes and biosynthetic strategies deployed to install this reactive moiety remain understudied. Herein, we report the use of in silico methods to identify enzymes with potential aziridine-installing (aziridinase) functionality. To validate candidates, we reconstitute enzymatic activity in vitro and demonstrate that an iron(IV)-oxo species initiates aziridine ring closure by the C-H bond cleavage. Furthermore, we divert the reaction pathway from aziridination to hydroxylation using mechanistic probes. This observation, isotope tracing experiments using H218O and 18O2, and quantitative product analysis, provide evidence for the polar capture of a carbocation species by the amine in the pathway to aziridine installation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Paris, Jared C |e verfasserin |4 aut | |
| 700 | 1 | |a Zanella, Brady |e verfasserin |4 aut | |
| 700 | 1 | |a Spletzer, Martha |e verfasserin |4 aut | |
| 700 | 1 | |a Yao, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Yisong |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Wei-Chen |e verfasserin |4 aut | |
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