Understanding the Enzyme (S)‑Norcoclaurine Synthase Promiscuity to Aldehydes and Ketones

The (S)-norcoclaurine synthase from Thalictrum flavum (TfNCS) stereoselectively catalyzes the Pictet–Spengler reaction between dopamine and 4-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. TfNCS can catalyze the Pictet–Spengler reaction with various aldehydes and ketones, leading to diverse te...

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Published in:	Journal of chemical information and modeling Vol. 64; no. 11; pp. 4462 - 4474
Main Authors:	Salvatti, Brunno A., Chagas, Marcelo A., Fernandes, Phillipe O., Ladeira, Yan F. X., Bozzi, Aline S., Valadares, Veronica S., Valente, Ana Paula, de Miranda, Amanda S., Rocha, Willian R., Maltarollo, Vinicius G., Moraes, Adolfo H.
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 10-06-2024
Subjects:	Aldehydes Aldehydes - chemistry Aldehydes - metabolism Biocatalysis Carbon-Nitrogen Ligases - chemistry Carbon-Nitrogen Ligases - metabolism Carbonyl compounds Carbonyl groups Carbonyls Computational Biochemistry Correlation Density functional theory Dopamine Electronic structure Enzymes Fine chemicals Ketones Ketones - chemistry Ketones - metabolism Libraries Machine learning Molecular dynamics Molecular Dynamics Simulation Molecular properties Molecular structure NMR Nuclear magnetic resonance Reactivity Substrate Specificity Substrates Thalictrum - chemistry Thalictrum - enzymology Thalictrum - metabolism
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Summary:	The (S)-norcoclaurine synthase from Thalictrum flavum (TfNCS) stereoselectively catalyzes the Pictet–Spengler reaction between dopamine and 4-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. TfNCS can catalyze the Pictet–Spengler reaction with various aldehydes and ketones, leading to diverse tetrahydroisoquinolines. This substrate promiscuity positions TfNCS as a highly promising enzyme for synthesizing fine chemicals. Understanding carbonyl-containing substrates’ structural and electronic signatures that influence TfNCS activity can help expand its applications in the synthesis of different compounds and aid in protein optimization strategies. In this study, we investigated the influence of the molecular properties of aldehydes and ketones on their reactivity in the TfNCS-catalyzed Pictet–Spengler reaction. Initially, we compiled a library of reactive and unreactive compounds from previous publications. We also performed enzymatic assays using nuclear magnetic resonance to identify some reactive and unreactive carbonyl compounds, which were then included in the library. Subsequently, we employed QSAR and DFT calculations to establish correlations between substrate-candidate structures and reactivity. Our findings highlight correlations of structural and stereoelectronic features, including the electrophilicity of the carbonyl group, to the reactivity of aldehydes and ketones toward the TfNCS-catalyzed Pictet–Spengler reaction. Interestingly, experimental data of seven compounds out of fifty-three did not correlate with the electrophilicity of the carbonyl group. For these seven compounds, we identified unfavorable interactions between them and the TfNCS. Our results demonstrate the applications of in silico techniques in understanding enzyme promiscuity and specificity, with a particular emphasis on machine learning methodologies, DFT electronic structure calculations, and molecular dynamic (MD) simulations.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1549-9596 1549-960X
DOI:	10.1021/acs.jcim.3c01773