On the Origin of the Different Reversible Characters of Salinosporamide A and Homosalinosporamide A in the Covalent Inhibition of the Human 20S Proteasome
Impacto
Scholar |
Otros documentos de la autoría: Serrano Aparicio, Natalia; Moliner, Vicent; Świderek, Katarzyna
Metadatos
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INVESTIGACIONMetadatos
Título
On the Origin of the Different Reversible Characters of Salinosporamide A and Homosalinosporamide A in the Covalent Inhibition of the Human 20S ProteasomeFecha de publicación
2021-09-17Editor
American Chemical SocietyISSN
2155-5435Cita bibliográfica
Serrano-Aparicio, N.; Moliner, V.; Świderek, K. On the Origin of the Different Reversible Characters of Salinosporamide A and Homosalinosporamide A in the Covalent Inhibition of the Human 20S Proteasome. ACS Catal. 2021,11,18, 11806-11819, DOI: 10.1021/acscatal.1c02614Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
https://pubs.acs.org/doi/full/10.1021/acscatal.1c02614Versión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
Covalent inhibition of the 20S proteasome is one of the strategies used in the fight against cancer, Chagas’ disease, malaria, tuberculosis, or neurodegenerative disorders. In this work, studies based on quantum ... [+]
Covalent inhibition of the 20S proteasome is one of the strategies used in the fight against cancer, Chagas’ disease, malaria, tuberculosis, or neurodegenerative disorders. In this work, studies based on quantum mechanics/molecular mechanics (M06-2X/AMBER) molecular dynamics simulations reveal, in agreement with experiments, that homosalinosporamide A (hSalA), contrary to the natural analogue, salinosporamide A (SalA), inhibits the β5 subunit in a reversible manner. The computed free energy landscapes indicate that either SalA or hSalA blocks the active site of the enzyme by a three-step process that includes two common chemical transformations. The last step of the inhibition with SalA, which is an intramolecular cyclization step that defines its irreversible character, was found to be energetically prohibited in the case of hSalA. In contrast, an additional chemical step was found that ensures neutralization of the negative charge accumulated during the β-lactone ring opening, thus providing a stable product of inhibition that agrees with X-ray diffraction studies. The weaker stabilization of this final product explains its reversible character that was further confirmed by exploring possible paths of hydrolysis of the covalent adduct. Finally, the rate-limiting step in both inhibitors corresponds to the nucleophilic attack of Thr1 on C1 carbon of the β-lactone. The identical activation free energies computed for SalA and hSalA agree with the undistinguishable experimentally measured values of IC50. [-]
Publicado en
ACS Catalysis, 2021, vol. 11, no 18Entidad financiadora
Ministerio de Ciencia e Innovación | Generalitat Valenciana | Universitat Jaume I | Ministerio de Economía y Competitividad (MINECO)
Código del proyecto o subvención
PGC2018-094852-B-C21 | PID2019-107098RJ-I00 | AICO/2019/195 and SEJI/2020/007 | UJI-B2020-03 | UJI-A2019-04 | BES-2016-078029
Derechos de acceso
Copyright © American Chemical Society
info:eu-repo/semantics/openAccess
info:eu-repo/semantics/openAccess
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