A computationally driven analysis of the polyphenol-protein interactome

Abstract

Polyphenol-rich foods are part of many nutritional interventions aimed at improving health and preventing cardiometabolic diseases (CMDs). Polyphenols have oxidative, inflammatory, and/or metabolic effects. Research into the chemistry and biology of polyphenol bioactives is prolific but knowledge of their molecular interactions with proteins is limited. We mined public data to (i) identify proteins that interact with or metabolize polyphenols, (ii) mapped these proteins to pathways and networks, and (iii) annotated functions enriched within the resulting polyphenol-protein interactome. A total of 1,395 polyphenols and their metabolites were retrieved (using Phenol-Explorer and Dictionary of Natural Products) of which 369 polyphenols interacted with 5,699 unique proteins in 11,987 interactions as annotated in STITCH, Pathway Commons, and BindingDB. Pathway enrichment analysis using the KEGG repository identified a broad coverage of significant pathways of low specificity to particular polyphenol (sub)classes. When compared to drugs or micronutrients, polyphenols have pleiotropic effects across many biological processes related to metabolism and CMDs. These systems-wide effects were also found in the protein interactome of the polyphenol-rich citrus fruits, used as a case study. In sum, these findings provide a knowledgebase for identifying polyphenol classes (and polyphenol-rich foods) that individually or in combination influence metabolism.

Divergent Effects of Daidzein and Its Metabolites on Estrogen-Induced Survival of Breast Cancer Cells

“…Like E2, D, D4S, and Eq trigger ERαS118 phosphorylation, even if only E2 reduces the receptor levels, an important mechanism for E2-induced cancer cell proliferation [34]. Moreover, ERα is necessary for D and its metabolites to regulate NGB levels, confirming that D and its metabolites could bind to and activate ERα, as already reported [3]. However, downstream of ERα activation, D and its metabolites trigger divergent signal pathways.…”

“…Due to their molecular structure and size, some of these molecules, including lignans, flavonoids, and stilbenes, have a chemical structure that resembles that of human estrogens, in particular to 17-β-estradiol (E2) [2]. Among other, isoflavones, a class of flavonoids ranked among the most estrogenic compounds, bind to estrogen receptor subtypes (i.e., ERα and ERβ) [3,4] exerting estrogenic and/or antiestrogenic effects [1]. For isoflavones, the key to their bioactivity in human and animals seems to rely on their (anti)estrogenic activity.…”

Daidzein Supplementation Enhances Embryos Survival by Improving Hormones, Antioxidant Capacity, and Metabolic Profiles of Amniotic Fluid in Sows

“…Previous study indicated that DAI can regulate the hypothalamic-pituitary-gonad axis of the endocrine system by competitively binding with estrogen receptors [17]. At the present study, we observed that daidzein supplementation signi cantly increased the levels of estrogen and tended to increase the activity of progesterone in the amniotic uid, which is consistent with a previous study that daidzein could improve estrogen and progesterone levels of female rat during pregnancy [19].…”

“…Daidzein (7,4′-dihydroxyiso avone, DAI) is a class of non-steroidal polyphenolic secondary metabolites, which has attracted considerable research interests because of their antioxidant, anti-in ammatory, and differentiation-inducing abilities [14][15][16]. Importantly, it can directly bind to estrogen receptor subtypes (i.e., ERα and ERβ) to exert estrogenic and/or antiestrogenic effects [17]. Extensive studies have focused on the role of daidzein on animal growth and health [18].…”

Analysis of a large food chemical database: chemical space, diversity, and complexity

“…The large list of polyphenols identified from FooDB is larger than the list of 1,395 polyphenols identified and used in the recent work of Lacroix et al . ( Lacroix et al ., 2018 ) that was retrieved from Phenol-Explorer and the Dictionary of Natural Products. Indeed, the list of 3,228 polyphenolic compound made available in this work can be used to augment the already extensive polyphenol-protein interactome work of Lacroix et al .…”