Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase

Sáez Ayala, Magalí; Chazarra Parres, Soledad; Cabezas Herrera, Juan; Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis

Publication:
Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase

dc.contributor.author	Sáez Ayala, Magalí
dc.contributor.author	Chazarra Parres, Soledad
dc.contributor.author	Cabezas Herrera, Juan
dc.contributor.author	Rodríguez López, José Neptuno
dc.contributor.author	Sánchez del Campo Ferrer, Luis
dc.contributor.department	Bioquímica y Biología Molecular A	es
dc.date.accessioned	2024-01-02T12:37:51Z
dc.date.available	2024-01-02T12:37:51Z
dc.date.issued	2009-12-18
dc.description	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.	es
dc.description.abstract	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.	es
dc.format	application/pdf	es
dc.format.extent	13	es
dc.identifier.citation	International Journal of Molecular Sciences. Volumen 10. nº12. Páginas 5398-5410
dc.identifier.doi	https://doi.org/10.3390/ijms10125398
dc.identifier.issn	1422-0067
dc.identifier.uri	http://hdl.handle.net/10201/136986
dc.language	eng	es
dc.publisher	MDPI	es
dc.relation	Ámbito del proyecto: Regional. Agencia financiadora: Fundación Séneca (CARM) Código o número del acuerdo de subvención: 08595/PI/08	es
dc.rights	info:eu-repo/semantics/openAccess	es
dc.rights	Atribución 4.0 Internacional	*
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	*
dc.subject	Polyphenols	es
dc.subject	Tea catechins	es
dc.subject	Flavonoids	es
dc.subject	Dihydrofolate reductase	es
dc.subject	Antifolates	es
dc.subject	Enzyme inhibition	es
dc.subject.other	CDU::5 - Ciencias puras y naturales::57 - Biología::577 - Bioquímica. Biología molecular. Biofísica	es
dc.title	Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase	es
dc.type	info:eu-repo/semantics/article	es
dspace.entity.type	Publication	es
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relation.isAuthorOfPublication.latestForDiscovery	36d7ac7e-b9a7-477c-8f7e-f03d4cc834c1