Glycoside Hydrolase Catalysis: Do Substrates and Mechanism-Based Covalent Inhibitors React via Matching Transition States?
Impacto
Scholar |
Otros documentos de la autoría: Akintola, Oluwafemi; Farren-Dai, Marco; Ren, Weiwu; Bhosale, Sandeep; Britton, Robert; Świderek, Katarzyna; Moliner, Vicent; Bennet, Andrew J.
Metadatos
Mostrar el registro completo del ítemcomunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/160292
comunitat-uji-handle3:10234/160293
comunitat-uji-handle4:
INVESTIGACIONMetadatos
Título
Glycoside Hydrolase Catalysis: Do Substrates and Mechanism-Based Covalent Inhibitors React via Matching Transition States?Autoría
Fecha de publicación
2023-12-02Editor
American Chemical SocietyISSN
2155-5435Cita bibliográfica
Akintola, O.; Farren-Dai, M.; Ren, W.; Bhosale, S.; Britton, R.; Świderek, K.; Moliner, M.; Bennet, A. J. Glycoside Hydrolase Catalysis: Do Substrates and Mechanism-Based Covalent Inhibitors React via Matching Transition States? ACS Catal. 2022, 12, 23, 14667–14678. DOI: 10.1021/acscatal.2c04027Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
https://pubs.acs.org/doi/full/10.1021/acscatal.2c04027Versión
info:eu-repo/semantics/acceptedVersionPalabras clave / Materias
Resumen
In this study, we look at how a catalytically efficient α-galactosidase stabilizes transition state (TS) charge delocalization for substrate hydrolysis. We then assess whether covalent inhibition of the enzyme by three ... [+]
In this study, we look at how a catalytically efficient α-galactosidase stabilizes transition state (TS) charge delocalization for substrate hydrolysis. We then assess whether covalent inhibition of the enzyme by three types of mechanism-based covalent inhibitors occurs via similar modes of TS stabilization. We show, using Bartlett-type linear free energy relationships, that good correlations are obtained between the catalytic efficiencies (kcat/Km and/or kinact/Ki) for enzyme-catalyzed reactions of natural and activated galactoside substrates and of representatives of three families of classical mechanism-based inhibitors: a 2-deoxy-2-fluoroglycoside, allylic carbasugars, and an epoxy carbasugar. Of note, we show that glycoside natural substrates and allylic carbasugars display log(rate)–log(rate) correlations that are unity (slope ≈ 1), an observation consistent with them having identical positive charge stabilization at the SN1-like glycosylation and pseudo-glycosylation TSs, respectively. In contrast, 2-deoxy-2-fluoroglycoside mechanism-based inhibitors react via a different enzyme-catalyzed mechanism (SN2), while the strained epoxy carbasugar inactivates the α-galactosidase by traversing a TS in which the glycoside hydrolase stabilizes the inactivation TS that has a significantly lower degree of charge stabilization to those for the natural glycoside substrates. To add weight to these conclusions, we computed free energy landscapes and their associated galactosylation and pseudo-galactosylation TSs using QM/MM molecular dynamics methods with the whole solvated enzyme. [-]
Publicado en
ACS Catalysis, 2022, vol. 12, no 23Entidad financiadora
Natural Sciences and Engineering Research Council of Canada | Ministerio de Ciencia, Innovación y Universidades | Generalitat Valenciana | Universitat Jaume I
Identificador de la entidad financiadora
http://dx.doi.org/10.13039/501100011033
Código del proyecto o subvención
2017-04910 | MICIU/ICTI2017-2020/PGC2021-23332OB-C21 | MICIU/ICTI2017-2020/PID2019-107098RJ-I00 | CIPROM/2021/079 | SEJI/2020/007 | UJI-A2019-04 | UJI-B2020-03 | RYC2020-030596-I
Título del proyecto o subvención
Estudios computacionales del mecanismo y la inhibición de la proteólisis enzimática como enfoque complementario del mundo del descubrimiento moderno de fármacos
Derechos de acceso
Copyright © American Chemical Society
http://rightsstatements.org/vocab/CNE/1.0/
info:eu-repo/semantics/openAccess
http://rightsstatements.org/vocab/CNE/1.0/
info:eu-repo/semantics/openAccess
Aparece en las colecciones
- INAM_Articles [510]