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  Regio‐ and Stereoselective Steroid Hydroxylation at C7 by Cytochrome P450 Monooxygenase Mutants

Li, A., Acevedo-Rocha, C. G., D'Amore, L., Chen, J., Peng, Y., Garcia‐Borràs, M., et al. (2020). Regio‐ and Stereoselective Steroid Hydroxylation at C7 by Cytochrome P450 Monooxygenase Mutants. Angewandte Chemie International Edition, 59(30), 12499-12505. doi:10.1002/anie.202003139.

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 Creators:
Li, Aitao1, Author
Acevedo-Rocha, Carlos G.2, Author
D'Amore, Lorenzo3, Author
Chen, Jinfeng4, Author
Peng, Yaqin1, Author
Garcia‐Borràs, Marc3, Author
Gao, Chenghua1, Author
Zhu, Jinmei1, Author
Rickerby, Harry5, Author
Osuna, Sílvia3, Author
Zhou, Jiahai4, Author
Reetz, Manfred T.6, 7, Author           
Affiliations:
1School of life science, Hubei University, State Key Laboratory of Biocatalysis and Enzyme Engineering, #368 Youyi Road, Wuhan, 430062 P.R. China, ou_persistent22              
2Biosyntia ApS, 2100, Copenhagen, Denmark, ou_persistent22              
3Institut de Química Computacional i Catàlisi and Departament de Química, Universitat de Girona, Carrer Maria Aurèlia Capmany 69, 17003 Girona, Catalonia, Spain, ou_persistent22              
4State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai, 200032 P. R. China, ou_persistent22              
5LabGenius, G.01-06 Cocoa Studios, 100 Drummond Rd, London, SE16 4DG UK, ou_persistent22              
6Research Department Reetz, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445588              
7Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, 32 West 7th Avenue, Tianjin, 300308 P. R. China, ou_persistent22              

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Free keywords: cytochromes; directed evolution; enzymes; oxidation; steroids
 Abstract: Steroidal C7β alcohols and their respective esters have shown significant promise as neuroprotective and anti‐inflammatory agents to treat chronic neuronal damage like stroke, brain trauma, and cerebral ischemia. Since C7 is spatially far away from any functional groups that could direct C−H activation, these transformations are not readily accessible using modern synthetic organic techniques. Reported here are P450‐BM3 mutants that catalyze the oxidative hydroxylation of six different steroids with pronounced C7 regioselectivities and β stereoselectivities, as well as high activities. These challenging transformations were achieved by a focused mutagenesis strategy and application of a novel technology for protein library construction based on DNA assembly and USER (Uracil‐Specific Excision Reagent) cloning. Upscaling reactions enabled the purification of the respective steroidal alcohols in moderate to excellent yields. The high‐resolution X‐ray structure and molecular dynamics simulations of the best mutant unveil the origin of regio‐ and stereoselectivity.

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Language(s): eng - English
 Dates: 2020-03-012020-04-032020-07-20
 Publication Status: Published in print
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1002/anie.202003139
 Degree: -

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Title: Angewandte Chemie International Edition
  Abbreviation : Angew. Chem., Int. Ed.
Source Genre: Journal
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Publ. Info: Weinheim : Wiley-VCH
Pages: - Volume / Issue: 59 (30) Sequence Number: - Start / End Page: 12499 - 12505 Identifier: ISSN: 1433-7851
CoNE: https://pure.mpg.de/cone/journals/resource/1433-7851