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Título: | Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase |
Fecha de publicación: | 18-dic-2009 |
Editorial: | MDPI |
Cita bibliográfica: | International Journal of Molecular Sciences. Volumen 10. nº12. Páginas 5398-5410 |
ISSN: | 1422-0067 |
Materias relacionadas: | CDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísica |
Palabras clave: | Polyphenols Tea catechins Flavonoids Dihydrofolate reductase Antifolates Enzyme inhibition |
Resumen: | Dihydrofolate reductase (DHFR) is the subject of intensive investigation since it appears to be the primary target enzyme for antifolate drugs. Fluorescence quenching experiments show that the ester bond-containing tea polyphenols (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG) are potent inhibitors of DHFR with dissociation constants (K-D) of 0.9 and 1.8 mu M, respectively, while polyphenols lacking the ester bound gallate moiety [e.g., (-)-epigallocatechin (EGC) and (-)-epicatechin (EC)] did not bind to this enzyme. To avoid stability and bioavailability problems associated with tea catechins we synthesized a methylated derivative of ECG (3-O-(3,4,5-trimethoxybenzoyl)(-)-epicatechin; TMECG), which effectively binds to DHFR (K-D = 2.1 mu M). In alkaline solution, TMECG generates a stable quinone methide product that strongly binds to the enzyme with a K-D of 8.2 nM. Quercetin glucuronides also bind to DHFR but its effective binding was highly dependent of the sugar residue, with quercetin-3-xyloside being the stronger inhibitor of the enzyme with a K-D of 0.6 mu M. The finding that natural polyphenols are good inhibitors of human DHFR could explain the epidemiological data on their prophylactic effects for certain forms of cancer and open a possibility for the use of natural and synthetic polyphenols in cancer chemotherapy. |
Autor/es principal/es: | Sánchez del Campo Ferrer, Luis Sáez Ayala, Magalí Chazarra Parres, Soledad Cabezas Herrera, Juan Rodríguez López, José Neptuno |
Facultad/Departamentos/Servicios: | Facultades, Departamentos, Servicios y Escuelas::Departamentos de la UMU::Bioquímica y Biología Molecular A |
URI: | http://hdl.handle.net/10201/136986 |
DOI: | https://doi.org/10.3390/ijms10125398 |
Tipo de documento: | info:eu-repo/semantics/article |
Número páginas / Extensión: | 13 |
Derechos: | info:eu-repo/semantics/openAccess Atribución 4.0 Internacional |
Descripción: | This is a Published version of the following article, in International Journal of Molecular Sciences. https://doi.org/10.3390/ijms10125398]. It is deposited under the terms of the Creative Commons Attribution-Non Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
Aparece en las colecciones: | Artículos: Bioquímica y Biología Molecular "A" |
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