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  Preparation of Structurally Diverse Chiral Alcohols by Engineering Ketoreductase CgKR

Zheng, G.-W., Liu, Y.-Y., Chen, Q., Huang, L., Yu, H.-L., Lou, W.-Y., et al. (2017). Preparation of Structurally Diverse Chiral Alcohols by Engineering Ketoreductase CgKR. ACS Catalysis, 7(10), 7174-7181. doi:10.1021/acscatal.7b01933.

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 Urheber:
Zheng, Gao-Wei1, Autor
Liu, Yuan-Yang1, Autor
Chen, Qi1, Autor
Huang, Lei1, Autor
Yu, Hui-Lei1, Autor
Lou, Wen-Yong2, Autor
Li, Chun-Xiu1, Autor
Bai, Yun-Peng1, Autor
Li, Aitao3, Autor           
Xu, Jian-He1, Autor
Affiliations:
1State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China, ou_persistent22              
2Lab of Applied Biocatalysis, School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, Guangdong, China, ou_persistent22              
3Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445588              

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Schlagwörter: asymmetric reduction; biocatalysis; chiral alcohol; ketoreductase; protein engineering; substrate specificity
 Zusammenfassung: Ketoreductases are tools for the synthesis of chiral alcohols in industry. However, the low activity of natural enzymes often restricts their use in industrial applications. On the basis of computational analysis and previous reports, two residues (F92 and F94) probably affecting the activity of ketoreductase CgKR1 were identified. By tuning these two residues, the CgKR1-F92C/F94W variant was obtained that exhibited higher activity toward all 28 structurally diverse substrates examined than the wild-type enzyme. Among them, 13 substrates have a specific activity over 50 U mg–1 (54–775 U mg–1). Using CgKR1-F92C/F94W as a catalyst, five substrates at high loading (>100 g–1 L–1) were reduced completely in gram-scale preparative reactions. This approach provides accesses to pharmaceutically relevant chiral alcohols with high enantioselectivity (up to 99.0% ee) and high space-time yield (up to 583 g–1 L–1 day–1). Molecular dynamics simulations highlighted the crucial role of residues 92 and 94 in activity improvement. Our findings provide useful guidance for engineering other ketoreductases, especially those possessing a similar active pocket to that in CgKR1.

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Sprache(n): eng - English
 Datum: 2017-06-142017-09-132017-10-06
 Publikationsstatus: Online veröffentlicht
 Seiten: 8
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1021/acscatal.7b01933
 Art des Abschluß: -

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Titel: ACS Catalysis
  Kurztitel : ACS Catal.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Washington, D.C. : American Chemical Society
Seiten: - Band / Heft: 7 (10) Artikelnummer: - Start- / Endseite: 7174 - 7181 Identifikator: Anderer: 2155-5435
CoNE: https://pure.mpg.de/cone/journals/resource/2155-5435