دورية أكاديمية
Improved Cyclopropanation Activity of Histidine-Ligated Cytochrome P450 Enables the Enantioselective Formal Synthesis of Levomilnacipran
| العنوان: | Improved Cyclopropanation Activity of Histidine-Ligated Cytochrome P450 Enables the Enantioselective Formal Synthesis of Levomilnacipran |
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| المؤلفون: | Wang, Jane Z., Renata, Hans, Peck, Nicole E., Farwell, Christopher C., Coelho, Pedro S., Arnold, Frances H. |
| المصدر: | Angewandte Chemie International Edition, 53(26), 6810-6813, (2014-06-23) |
| بيانات النشر: | Wiley |
| سنة النشر: | 2014 |
| المجموعة: | Caltech Authors (California Institute of Technology) |
| مصطلحات موضوعية: | biocatalysis, cyclopropanation, cytochrome P450, enzymes, protein engineering |
| الوصف: | Engineering enzymes capable of modes of activation unprecedented in nature will increase the range of industrially important molecules that can be synthesized through biocatalysis. However, low activity for a new function is often a limitation in adopting enzymes for preparative-scale synthesis, reaction with demanding substrates, or when a natural substrate is also present. By mutating the proximal ligand and other key active-site residues of the cytochrome P450 enzyme from Bacillus megaterium (P450-BM3), a highly active His-ligated variant of P450-BM3 that can be employed for the enantioselective synthesis of the levomilnacipran core was engineered. This enzyme, BM3-Hstar, catalyzes the cyclopropanation of N,N-diethyl-2-phenylacrylamide with an estimated initial rate of over 1000 turnovers per minute and can be used under aerobic conditions. Cyclopropanation activity is highly dependent on the electronic properties of the P450 proximal ligand, which can be used to tune this non-natural enzyme activity. ; © 2014 Wiley-VCH Verlag GmbH & Co. Article first published online: 6 May 2014. Manuscript Received: 26 Feb 2014. We thank Dr. S. Virgil and the Center for Catalysis and Chemical Synthesis (3CS) at Caltech for assistance with HPLC, Dr. J. McIntosh and Dr. T. Heel for helpful discussions, and R. Kitto for help during preparative-scale reactions. This work was supported by the Gordon and Betty Moore Foundation through Grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative. Z.J.W. was supported by a Ruth L. Kirschstein Fellowship from the National Institutes of Health, award number F32EB015846-01. ; Accepted Version - nihms602991.pdf |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| العلاقة: | https://doi.org/10.1002/anie.201402809Test; oai:authors.library.caltech.edu:5d9zg-ym995; https://www.ncbi.nlm.nih.gov/pmc/PMC4120663Test; eprintid:45663; resolverid:CaltechAUTHORS:20140512-091600678 |
| DOI: | 10.1002/anie.201402809 |
| الإتاحة: | https://doi.org/10.1002/anie.201402809Test https://www.ncbi.nlm.nih.gov/pmc/PMC4120663Test |
| حقوق: | info:eu-repo/semantics/openAccess ; Other |
| رقم الانضمام: | edsbas.4C2EB07E |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/anie.201402809 |
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