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Biocatalytic Synthesis of Ruxolitinib Intermediate via Engineered Imine Reductase.
Huang, Aiping; Zhang, Xuewen; Yang, Yiming; Shi, Chengcheng; Zhang, Bifei; Tuo, Xinkun; Shen, Peili; Jiao, Xuecheng; Zhang, Na.
Afiliação
  • Huang A; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Zhang X; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Yang Y; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Shi C; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Zhang B; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Tuo X; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Shen P; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Jiao X; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
  • Zhang N; Center of Biosynthesis Technology, Asymchem Life Science (Tianjin) Co, Ltd, Tianjin 300457, P.R. China.
J Org Chem ; 89(16): 11446-11454, 2024 08 16.
Article em En | MEDLINE | ID: mdl-39113180
ABSTRACT
An enzyme catalyzed strategy for the synthesis of a chiral hydrazine from 3-cyclopentyl-3-oxopropanenitrile 5 and hydrazine hydrate 2 is presented. An imine reductase (IRED) from Streptosporangium roseum was identified to catalyze the reaction between 3-cyclopentyl-3-oxopropanenitrile 5 and hydrazine hydrate 2 to produce trace amounts of (R)-3-cyclopentyl-3-hydrazineylpropanenitrile 4. We employed a 2-fold approach to optimize the catalytic performance of this enzyme. First, a transition state analogue (TSA) model was constructed to illuminate the enzyme-substrate interactions. Subsequently, the Enzyme_design and Funclib methods were utilized to predict mutants for experimental evaluation. Through three rounds of site-directed mutagenesis, site saturation mutagenesis, and combinatorial mutagenesis, we obtained mutant M6 with a yield of 98% and an enantiomeric excess (ee) of 99%. This study presents an effective method for constructing a hydrazine derivative via IRED-catalyzed reductive amination of ketone and hydrazine. Furthermore, it provides a general approach for constructing suitable enzymes, starting from nonreactive enzymes and gradually enhancing their catalytic activity through active site modifications.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases / Pirazóis / Pirimidinas / Biocatálise / Nitrilas Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases / Pirazóis / Pirimidinas / Biocatálise / Nitrilas Idioma: En Ano de publicação: 2024 Tipo de documento: Article