[en] Promoting endogenous neurogenesis for brain repair is emerging as a promising strategy to mitigate the functional impairments associated with various neurological disorders characterized by neuronal death. Diterpenes featuring tigliane, ingenane, jatrophane and lathyrane skeletons, frequently found in Euphorbia plant species, are known protein kinase C (PKC) activators and exhibit a wide variety of pharmacological properties, including the stimulation of neurogenesis. Microbial transformation of these diterpenes represents a green and sustainable methodology that offers a hitherto little explored approach to obtaining novel derivatives and exploring structure-activity relationships. In the present study, we report the biotransformation of euphoboetirane A (4) and epoxyboetirane A (5), two lathyrane diterpenoids isolated from Euphorbia boetica, by Mucor circinelloides MC NRRL3631. Our findings revealed the production of nine biotransformation products (6-14), including jatrophane derivatives originated through an unprecedented rearrangement from the parent lathyranes. The chemical structures and absolute configurations of the new compounds were elucidated through comprehensive analysis using NMR and ECD spectroscopy, as well as MS. The study evaluated how principal metabolites and their derivatives affect TGFα and NRG1 release, as well as their potential to promote proliferation or differentiation in cultures of NSC isolated from the SVZ of adult mice. In order to shed some light on the mechanisms underlying the ability of 12 as a neurogenic compound, the interactions of selected compounds with PKC δ-C1B were analyzed through molecular docking and molecular dynamics. Based on these, it clearly appears that the ability of compound 12 to form both acceptor and donor hydrogen bonds with certain amino acid residues in the enzyme pocket leads to a higher affinity compound-PKC complex, which correlates with the observed biological activity.
Escobar-Montaño, Felipe; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real Cádiz, Spain
Gómez Oliva, Ricardo ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Molecular Regulation of Neurogenesis ; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain, Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Ezzanad, Abdellah; Instituto Universitario de Investigación en Biomoléculas, Universidad de Cádiz, Puerto Real Cádiz, Spain
Vázquez de Górgolas, Sonia; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain
Zorrilla, David; Departamento de Química Física, Facultad de Ciencias, Universidad de Cádiz, Puerto Real Cádiz, Spain, Instituto Universitario de Microscopía Electrónica y Materiales, Universidad de Cádiz, Puerto Real Cádiz, Spain
Macías-Sánchez, Antonio J; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real Cádiz, Spain, Instituto Universitario de Investigación en Biomoléculas, Universidad de Cádiz, Puerto Real Cádiz, Spain
Botubol-Ares, José M; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real Cádiz, Spain, Instituto Universitario de Investigación Vitivinícola y Agroalimentaria, Universidad de Cádiz, Puerto Real Cádiz, Spain. Electronic address: josemanuel.botubol@uca.es
Nunez-Abades, Pedro; Departamento de Fisiología, Universidad de Sevilla, Sevilla, Spain
Castro, Carmen; Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain, Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Cádiz, Spain
Durán-Patrón, Rosa; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real Cádiz, Spain, Instituto Universitario de Investigación en Biomoléculas, Universidad de Cádiz, Puerto Real Cádiz, Spain. Electronic address: rosa.duran@uca.es
Hernández-Galán, Rosario; Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Cádiz, Puerto Real Cádiz, Spain, Instituto Universitario de Investigación en Biomoléculas, Universidad de Cádiz, Puerto Real Cádiz, Spain
Language :
English
Title :
Effect of lathyrane-type diterpenoids in neural stem cell physiology: Microbial transformations, molecular docking and dynamics studies.
Junta de Andalucía MICINN - Ministerio de Ciencia, Innovación y Universidades
Funding text :
This research was co-financed by grants PID2022-142418OB-C22 and PID2022-142418OB-C21, funded by MCIN/AEI/ 10.13039/501100011033 and ERDF Operational Program, and by grant P18-RT-2655, funded by the Department of Economic Transformation, Industry, Knowledge, and Universities of the Regional Government of Andalusia.
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