Theoretical investigation of the Pictet-Spengler reaction between dopamine and (S)-citronellal catalyzed by the enzyme (S)-norcoclaurine synthase

• Autor(a) principal: Aline de Souza Bozzi
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Institucional da UFMG
• Texto Completo: http://hdl.handle.net/1843/38629; https://orcid.org/0000-0002-6386-6667
• topic: Norcoclaurine Synthase; Reaction Mechanism; Dopamine; (S)citronellal; Molecular Docking; Molecular Dynamics; Density Functional Theory; Norcoclaurina sintase; Dopamina; (S) citronelal; Ancoramento molecular; Simulação de dinâmica molecular clássica; Teoria do funcional da densidade; Mecanismo de reação; Físico-química; Enzimas; Dopamina; Aldeídos; Cetonas; Funcionais de densidade; Dinâmica molecular; Mecanismos de reação (Química)

The Norcoclaurine Synthase enzyme is known to be the Pictet-Spenglerase responsible for catalyzing the condensation of dopamine and 4-hydroxyphenylacetaldehyde, leading to the formation of s-norcoclaurine, the first metabolite in the biosynthesis of benzylisoquinoline alkaloids. Recently, the Norcoclaurine Synthase has shown great promiscuity towards many aldehyde and ketone substrates, raising great interest in further understandings. In this work, we computationally investigate the structural aspects of this enzyme regarded to the substrate (S)-citronellal, a long-chain aliphatic aldehyde that contrasts with the natural aldehyde, 4-hydroxyphenylacetaldehyde. Furthermore, we also investigated the mechanism of a condensation reaction between dopamine and (S)citronellal catalyzed by the Norcoclaurina Synthase. For that, we employed molecular docking methodologies, classical molecular dynamics simulation, and density functional theory. We demonstrate through molecular docking and molecular dynamics simulations that the preferential enzyme-substrate binding mode presents the dopamine more deeply anchored in the active site, interacting with the amino acid LYS122 in a conformation considered active, meaning it will favor the occurrence of the reaction. Also, the (S)citronellal occupies the cavity entrance, having part of its chain solvent-exposed, which may be indicative of the promiscuity of the enzyme concerning the carbonylated compounds. From a mechanistic aspect, through density functional theory and cluster methodology, we showed that the reaction path has three fewer intermediates than the previously published one. Furthermore, we also found that the conformational constraints experienced by the substrates considerably alter the activation energy barrier for the cyclization step.