Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase
Abstract Norcoclaurine synthase from Thalictrum flavum (TfNCS) demonstrated high stereospecificity and yield in catalyzing the Pictet-Spengler reaction of dopamine with chiral aldehydes, achieving kinetic resolution of aldehydes. However, the mechanism and the factors contributing to the stereoselec...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-03-01
|
| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-024-01146-x |
| _version_ | 1797233733700419584 |
|---|---|
| author | Shiqing Zhang Chenghua Zhang Aijing Guo Baoyan Liu Hao Su Xiang Sheng |
| author_facet | Shiqing Zhang Chenghua Zhang Aijing Guo Baoyan Liu Hao Su Xiang Sheng |
| author_sort | Shiqing Zhang |
| collection | DOAJ |
| description | Abstract Norcoclaurine synthase from Thalictrum flavum (TfNCS) demonstrated high stereospecificity and yield in catalyzing the Pictet-Spengler reaction of dopamine with chiral aldehydes, achieving kinetic resolution of aldehydes. However, the mechanism and the factors contributing to the stereoselectivity remain unclear. Herein, by using quantum chemical calculations, the mechanisms of TfNCS-catalyzed reactions of dopamine with both enantiomers of α-methyl-phenylacetaldehyde are studied. The calculations reveal a mechanism mirroring the reaction of natural substrates, for which the deprotonation of the C5−H of the cyclized intermediate is rate-limiting. The calculated overall barriers are 20.1 kcal mol-1 and 21.6 kcal mol-1 for the reactions of (R)- and (S)-α-methyl-phenylacetaldehyde, respectively. The M97 and L72 residues are proposed to be the key residues contributing to the stereospecificity. The obtained detailed information is helpful for designing new variants of TfNCS with extended substrate scope, and also advancing our understanding of TfNCS reactions for potential applications. |
| first_indexed | 2024-04-24T16:20:52Z |
| format | Article |
| id | doaj.art-3af641cbfeaa4b9395072728d7f863ee |
| institution | Directory Open Access Journal |
| issn | 2399-3669 |
| language | English |
| last_indexed | 2024-04-24T16:20:52Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj.art-3af641cbfeaa4b9395072728d7f863ee2024-03-31T11:12:33ZengNature PortfolioCommunications Chemistry2399-36692024-03-01711710.1038/s42004-024-01146-xComputational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthaseShiqing Zhang0Chenghua Zhang1Aijing Guo2Baoyan Liu3Hao Su4Xiang Sheng5Tianjin Institute of Industrial Biotechnology, Chinese Academy of SciencesTianjin Institute of Industrial Biotechnology, Chinese Academy of SciencesTianjin Institute of Industrial Biotechnology, Chinese Academy of SciencesTianjin Institute of Industrial Biotechnology, Chinese Academy of SciencesTianjin Institute of Industrial Biotechnology, Chinese Academy of SciencesTianjin Institute of Industrial Biotechnology, Chinese Academy of SciencesAbstract Norcoclaurine synthase from Thalictrum flavum (TfNCS) demonstrated high stereospecificity and yield in catalyzing the Pictet-Spengler reaction of dopamine with chiral aldehydes, achieving kinetic resolution of aldehydes. However, the mechanism and the factors contributing to the stereoselectivity remain unclear. Herein, by using quantum chemical calculations, the mechanisms of TfNCS-catalyzed reactions of dopamine with both enantiomers of α-methyl-phenylacetaldehyde are studied. The calculations reveal a mechanism mirroring the reaction of natural substrates, for which the deprotonation of the C5−H of the cyclized intermediate is rate-limiting. The calculated overall barriers are 20.1 kcal mol-1 and 21.6 kcal mol-1 for the reactions of (R)- and (S)-α-methyl-phenylacetaldehyde, respectively. The M97 and L72 residues are proposed to be the key residues contributing to the stereospecificity. The obtained detailed information is helpful for designing new variants of TfNCS with extended substrate scope, and also advancing our understanding of TfNCS reactions for potential applications.https://doi.org/10.1038/s42004-024-01146-x |
| spellingShingle | Shiqing Zhang Chenghua Zhang Aijing Guo Baoyan Liu Hao Su Xiang Sheng Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase Communications Chemistry |
| title | Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase |
| title_full | Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase |
| title_fullStr | Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase |
| title_full_unstemmed | Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase |
| title_short | Computational mechanistic investigation of the kinetic resolution of α-methyl-phenylacetaldehyde by norcoclaurine synthase |
| title_sort | computational mechanistic investigation of the kinetic resolution of α methyl phenylacetaldehyde by norcoclaurine synthase |
| url | https://doi.org/10.1038/s42004-024-01146-x |
| work_keys_str_mv | AT shiqingzhang computationalmechanisticinvestigationofthekineticresolutionofamethylphenylacetaldehydebynorcoclaurinesynthase AT chenghuazhang computationalmechanisticinvestigationofthekineticresolutionofamethylphenylacetaldehydebynorcoclaurinesynthase AT aijingguo computationalmechanisticinvestigationofthekineticresolutionofamethylphenylacetaldehydebynorcoclaurinesynthase AT baoyanliu computationalmechanisticinvestigationofthekineticresolutionofamethylphenylacetaldehydebynorcoclaurinesynthase AT haosu computationalmechanisticinvestigationofthekineticresolutionofamethylphenylacetaldehydebynorcoclaurinesynthase AT xiangsheng computationalmechanisticinvestigationofthekineticresolutionofamethylphenylacetaldehydebynorcoclaurinesynthase |