Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens
Autor(a) principal: | |
---|---|
Data de Publicação: | 2008 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/5837 https://doi.org/10.1016/j.jsbmb.2007.10.011 |
Resumo: | High levels of endogenous estrogens are associated with increased risks of breast cancer. Estrogen levels are mainly increased by the activity of the aromatase enzyme and reduced by oxidative/conjugative metabolic pathways. In this paper, we demonstrate for the first time that catechol estrogen metabolites are potent aromatase inhibitors, thus establishing a link between aromatase activity and the processes involved in estrogen metabolism. In particular, the anti-aromatase activity of a set of natural hydroxyl and methoxyl estrogen metabolites was investigated using biochemical methods and subsequently compared with the anti-aromatase potency of estradiol and two reference aromatase inhibitors. Catechol estrogens proved to be strong inhibitors with an anti-aromatase potency two orders of magnitude higher than estradiol. A competitive inhibition mechanism was found for the most potent molecule, 2-hydroxyestradiol (2-OHE2) and a rational model identifying the interaction determinants of the metabolites with the enzyme is proposed based on ab initio quantum-mechanical calculations. A strong relationship between activity and electrostatic properties was found for catechol estrogens. Moreover, our results suggest that natural catechol estrogens may be involved in the control mechanisms of estrogen production. |
id |
RCAP_61dd3bf17e612fb52bfa7be7844b4256 |
---|---|
oai_identifier_str |
oai:estudogeral.uc.pt:10316/5837 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogensBreast cancerAromatase inhibitionEstradiol metabolitesCatechol estrogensStructure-activity relationshipsElectrostatic surface potentialHigh levels of endogenous estrogens are associated with increased risks of breast cancer. Estrogen levels are mainly increased by the activity of the aromatase enzyme and reduced by oxidative/conjugative metabolic pathways. In this paper, we demonstrate for the first time that catechol estrogen metabolites are potent aromatase inhibitors, thus establishing a link between aromatase activity and the processes involved in estrogen metabolism. In particular, the anti-aromatase activity of a set of natural hydroxyl and methoxyl estrogen metabolites was investigated using biochemical methods and subsequently compared with the anti-aromatase potency of estradiol and two reference aromatase inhibitors. Catechol estrogens proved to be strong inhibitors with an anti-aromatase potency two orders of magnitude higher than estradiol. A competitive inhibition mechanism was found for the most potent molecule, 2-hydroxyestradiol (2-OHE2) and a rational model identifying the interaction determinants of the metabolites with the enzyme is proposed based on ab initio quantum-mechanical calculations. A strong relationship between activity and electrostatic properties was found for catechol estrogens. Moreover, our results suggest that natural catechol estrogens may be involved in the control mechanisms of estrogen production.http://www.sciencedirect.com/science/article/B6T8X-4RW435B-1/1/e10135327f6ef1e2c98b343e9e9b8f252008info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleaplication/PDFhttp://hdl.handle.net/10316/5837http://hdl.handle.net/10316/5837https://doi.org/10.1016/j.jsbmb.2007.10.011engThe Journal of Steroid Biochemistry and Molecular Biology. 110:1-2 (2008) 10-17Neves, Marco A. C.Dinis, Teresa C. P.Colombo, GiorgioMelo, M. Luísa Sá einfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-05-25T03:49:16Zoai:estudogeral.uc.pt:10316/5837Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:25.763780Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens |
title |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens |
spellingShingle |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens Neves, Marco A. C. Breast cancer Aromatase inhibition Estradiol metabolites Catechol estrogens Structure-activity relationships Electrostatic surface potential |
title_short |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens |
title_full |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens |
title_fullStr |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens |
title_full_unstemmed |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens |
title_sort |
Biochemical and computational insights into the anti-aromatase activity of natural catechol estrogens |
author |
Neves, Marco A. C. |
author_facet |
Neves, Marco A. C. Dinis, Teresa C. P. Colombo, Giorgio Melo, M. Luísa Sá e |
author_role |
author |
author2 |
Dinis, Teresa C. P. Colombo, Giorgio Melo, M. Luísa Sá e |
author2_role |
author author author |
dc.contributor.author.fl_str_mv |
Neves, Marco A. C. Dinis, Teresa C. P. Colombo, Giorgio Melo, M. Luísa Sá e |
dc.subject.por.fl_str_mv |
Breast cancer Aromatase inhibition Estradiol metabolites Catechol estrogens Structure-activity relationships Electrostatic surface potential |
topic |
Breast cancer Aromatase inhibition Estradiol metabolites Catechol estrogens Structure-activity relationships Electrostatic surface potential |
description |
High levels of endogenous estrogens are associated with increased risks of breast cancer. Estrogen levels are mainly increased by the activity of the aromatase enzyme and reduced by oxidative/conjugative metabolic pathways. In this paper, we demonstrate for the first time that catechol estrogen metabolites are potent aromatase inhibitors, thus establishing a link between aromatase activity and the processes involved in estrogen metabolism. In particular, the anti-aromatase activity of a set of natural hydroxyl and methoxyl estrogen metabolites was investigated using biochemical methods and subsequently compared with the anti-aromatase potency of estradiol and two reference aromatase inhibitors. Catechol estrogens proved to be strong inhibitors with an anti-aromatase potency two orders of magnitude higher than estradiol. A competitive inhibition mechanism was found for the most potent molecule, 2-hydroxyestradiol (2-OHE2) and a rational model identifying the interaction determinants of the metabolites with the enzyme is proposed based on ab initio quantum-mechanical calculations. A strong relationship between activity and electrostatic properties was found for catechol estrogens. Moreover, our results suggest that natural catechol estrogens may be involved in the control mechanisms of estrogen production. |
publishDate |
2008 |
dc.date.none.fl_str_mv |
2008 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/5837 http://hdl.handle.net/10316/5837 https://doi.org/10.1016/j.jsbmb.2007.10.011 |
url |
http://hdl.handle.net/10316/5837 https://doi.org/10.1016/j.jsbmb.2007.10.011 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
The Journal of Steroid Biochemistry and Molecular Biology. 110:1-2 (2008) 10-17 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
aplication/PDF |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799133751222992896 |