| Texto completo | |
| Autor(es): |
Curtolo, Felipe
;
Arantes, Guilherme M.
Número total de Autores: 2
|
| Tipo de documento: | Artigo Científico |
| Fonte: | JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 63, n. 11, p. 11-pg., 2023-05-17. |
| Resumo | |
The interconversion between fumarate and succinate isfundamentalto the energy metabolism of nearly all organisms. This redox reactionis catalyzed by a large family of enzymes, fumarate reductases andsuccinate dehydrogenases, using hydride and proton transfers froma flavin cofactor and a conserved Arg side-chain. These flavoenzymesalso have substantial biomedical and biotechnological importance.Therefore, a detailed understanding of their catalytic mechanismsis valuable. Here, calibrated electronic structure calculations ina cluster model of the active site of the Fcc(3) fumaratereductase were employed to investigate various reaction pathways andpossible intermediates in the enzymatic environment and to dissectinteractions that contribute to catalysis of fumarate reduction. Carbanion,covalent adduct, carbocation, and radical intermediates were examined.Significantly lower barriers were obtained for mechanisms via carbanionintermediates, with similar activation energies for hydride and protontransfers. Interestingly, the carbanion bound to the active site isbest described as an enolate. Hydride transfer is stabilized by apreorganized charge dipole in the active site and by the restrictionof the C1-C2 bond in a twisted conformation of the otherwiseplanar fumarate dianion. But, protonation of a fumarate carboxylateand quantum tunneling effects are not critical for catalysis of thehydride transfer. Calculations also suggest that the driving forcefor enzyme turnover is provided by regeneration of the catalytic Arg,either coupled with flavin reduction and decomposition of a proposedtransient state or directly from the solvent. The detailed mechanisticdescription of enzymatic reduction of fumarate provided here clarifiesprevious contradictory views and provides new insights into catalysisby essential flavoenzyme reductases and dehydrogenases. (AU) | |
| Processo FAPESP: | 17/26109-0 - Simulação computacional de reatividade e transferência de elétrons no complexo II respiratório |
| Beneficiário: | Felipe Curtolo |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado Direto |
| Processo FAPESP: | 16/23525-0 - Simulação computacional dos mecanismos de reação em quinol:fumarato redutases |
| Beneficiário: | Felipe Curtolo |
| Modalidade de apoio: | Bolsas no Brasil - Mestrado |
| Processo FAPESP: | 23/00934-5 - Metodologias computacionais para simulação de transferência acoplada próton-elétron em biomoléculas |
| Beneficiário: | Guilherme Menegon Arantes |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 19/21856-7 - Bioenergética molecular computacional |
| Beneficiário: | Guilherme Menegon Arantes |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |