- Reprogramming Epoxide Hydrolase to Improve Enantioconvergence in Hydrolysis of Styrene Oxide Scaffolds
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Enantioconvergent hydrolysis by epoxide hydrolase is a promising method for the synthesis of important vicinal diols. However, the poor regioselectivity of the naturally occurring enzymes results in low enantioconvergence in the enzymatic hydrolysis of styrene oxides. Herein, modulated residue No. 263 was redesigned based on structural information and a smart variant library was constructed by site-directed modification using an “optimized amino acid alphabet” to improve the regioselectivity of epoxide hydrolase from Vigna radiata (VrEH2). The regioselectivity coefficient (r) of variant M263Q for the R-isomer of meta-substituted styrene oxides was improved 40–63-fold, and variant M263V also exhibited higher regioselectivity towards the R-isomer of para-substituted styrene oxides compared with the wild type, which resulted in improved enantioconvergence in hydrolysis of styrene oxide scaffolds. Structural insight showed the crucial role of residue No. 263 in modulating the substrate binding conformation by altering the binding surroundings. Furthermore, increased differences in the attacking distance between nucleophilic residue Asp101 and the two carbon atoms of the epoxide ring provided evidence for improved regioselectivity. Several high-value vicinal diols were readily synthesized (>88% yield, 90%–98% ee) by enantioconvergent hydrolysis using the reprogrammed variants. These findings provide a successful strategy for enhancing the enantioconvergence of native epoxide hydrolases through key single-site mutation and more powerful enzyme tools for the enantioconvergent hydrolysis of styrene oxide scaffolds into single (R)-enantiomers of chiral vicinal diols. (Figure presented.).
- Li, Fu-Long,Qiu, Yan-Yan,Zheng, Yu-Cong,Chen, Fei-Fei,Kong, Xu–Dong,Xu, Jian-He,Yu, Hui-Lei
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supporting information
p. 4699 - 4706
(2020/09/21)
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- OXIME COMPOUNDS AND THE USE THEREOF
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The invention relates to oxime compounds of Formula (I) and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein X is hydrogen, optionally substituted aryl, optionally substituted heteroaryl or the like; Y is CO, SO2, CRsu
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Page/Page column 367
(2008/06/13)
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- Bacterial monooxygenase mediated preparation of nonracemic chiral oxiranes: Study of the effects of substituent nature and position
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Monooxygenation of styrene derivatives using recombinant E. coli biocatalyst is an efficient way to prepare the corresponding oxiranes. The electronic and geometric effects of the ring substituents are described and show the relaxed specificity of the enzyme and its high stereoselectivity.
- Bernasconi, Silvana,Orsini, Fulvia,Sello, Guido,Di Gennaro, Patrizia
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p. 1603 - 1606
(2007/10/03)
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- Discovery and initial structure-activity relationships of trisubstituted ureas as thrombin receptor (PAR-1) antagonists
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Thrombin is the most potent agonist of platelet activation, and its effects are predominantly mediated by platelet thrombin receptors. Therefore, antagonists of the thrombin receptor have potential utility for the treatment of thrombotic disorders. Screening of combinatorial libraries revealed 2 to be a potent antagonist of the thrombin receptor. Modifications of this structure produced 11k, which inhibits thrombin receptor stimulated secretion and aggregation of platelets.
- Barrow, James C,Nantermet, Philippe G,Selnick, Harold G,Glass, Kristen L,Ngo, Phung L,Young, Mary Beth,Pellicore, Janetta M,Breslin, Michael J,Hutchinson, John H,Freidinger, Roger M,Condra, Cindra,Karczewski, Jerzy,Bednar, Rodney A,Gaul, Stanley L,Stern, Andrew,Gould, Robert,Connolly, Thomas M
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p. 2691 - 2696
(2007/10/03)
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