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Bimolecular Nucleophilic Substitution (SN2) Reaction Catalyzed by l-Threonine Aldolase

文献类型：期刊论文

作者Yang, Huijun4,5; Li, Qinrou2,3; Wang, Shiping2,3; Zhang, Rui4; Sheng, Xiang1,3; Liao, Cangsong4,5
刊名JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
出版日期2025-08-27
卷号147期号:34页码:30863-30872
ISSN号0002-7863
DOI10.1021/jacs.5c07660
通讯作者Zhang, Rui(zhangrui4@simm.ac.cn) ; Sheng, Xiang(shengx@tib.cas.cn) ; Liao, Cangsong(csliao@simm.ac.cn)
英文摘要The bimolecular nucleophilic substitution (S(N)2) and aldol reactions are cornerstone transformations in organic and biochemical synthesis, yet they operate through fundamentally distinct mechanisms, substrates, and product frameworks. Nature has evolved dedicated enzyme families to catalyze these reactions separately, namely, aldolases for aldol condensations and methyltransferases or similar enzymes for S(N)2 pathways. Aldolases have not been reported to catalyze S(N)2 reactions. We herein report the unprecedented repurposing of l-threonine aldolase to catalyze an S(N)2 reaction. This new activity enables direct asymmetric alkylation of the sp(3)-hybridized C alpha-H bond in glycine using readily accessible alpha-halide carbonyl compounds. Mechanistic and computational analyses elucidate how the active site of the enzyme precisely aligns substrates into a geometry that facilitates the S(N)2 transition state. The developed biocatalytic platform provides efficient access to diverse enantiomerically enriched alpha-amino acids (29 examples), achieving yields up to 95% and exceptional stereocontrol (e.r. > 99:1). This discovery not only expands the catalytic repertoire of aldolases but also underscores the potential for repurposing aldolases to unlock non-native reactivities in sustainable synthesis.
WOS关键词DEPENDENT ENZYME ; MECHANISM ; BIOSYNTHESIS ; ACID ; BRAIN
资助项目National Natural Science Foundation of China[22161132029] ; National Natural Science Foundation of China[YSBR-072-1] ; CAS Project for Young Scientists in Basic Research[22HHSWSS00020] ; Innovation Fund of Haihe Laboratory of Synthetic Biology[XDB1060000] ; Strategic Priority Research Program of the Chinese Academy of Sciences ; Shanghai Institute of Materia Medica ; Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001551048500001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/321282]  
专题中国科学院上海药物研究所
通讯作者Zhang, Rui; Sheng, Xiang; Liao, Cangsong
作者单位1.Natl Ctr Technol Innovat Synthet Biol, Tianjin 300308, Peoples R China
2.Haihe Lab Synthet Biol, Tianjin 300308, Peoples R China
3.Chinese Acad Sci, Tianjin Inst Ind Biotechnol, State Key Lab Engn Biol Low Carbon Mfg, Tianjin 300308, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Huijun,Li, Qinrou,Wang, Shiping,et al. Bimolecular Nucleophilic Substitution (SN2) Reaction Catalyzed by l-Threonine Aldolase[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(34):30863-30872.
APA Yang, Huijun,Li, Qinrou,Wang, Shiping,Zhang, Rui,Sheng, Xiang,&Liao, Cangsong.(2025).Bimolecular Nucleophilic Substitution (SN2) Reaction Catalyzed by l-Threonine Aldolase.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(34),30863-30872.
MLA Yang, Huijun,et al."Bimolecular Nucleophilic Substitution (SN2) Reaction Catalyzed by l-Threonine Aldolase".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.34(2025):30863-30872.

入库方式： OAI收割

来源：上海药物研究所

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