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  • In silico modelling studies might aid our understanding

    2019-07-12

    In silico modelling studies might aid our understanding of the functionality and potential biological activity of food and, in the long-term they might underpin the development of personalised diets to reduce health risks and help us to better understand pharmaceutical/food interactions.
    Acknowledgments We thank Dr. Wanting Jiao for her help with the molecular modelling studies. HY received a China Scholarship Council award for his doctoral studies in New Zealand.
    Introduction: promiscuity in steroids that activate the estrogen receptor As our understanding of ligand-protein interactions has expanded, appreciation for the role of promiscuity as a force in evolution has increased [[1], [2], [3], [4], [5]]. The term ‘promiscuity’ is akin to that of ‘biological messiness’ [6]. We use promiscuity here as the capacity of the estrogen receptor (ER) to bind physiological steroids with diverse structures. In particular, the A ring of estradiol (E2), the main physiological estrogen, differs from the A ring in Δ5-androstenediol, 5α-androstanediol, and 27-hydroxycholesterol (Fig. 1), as well as from the A ring of other Molidustat of vertebrate adrenal and sex steroids (Fig. 2). Indeed, the aromatic A ring and C3 phenolic group, characteristic of E2, have been exploited to synthesize ‘synthetic estrogens’ that are used to treat estrogen-dependent diseases (Fig. 3) [7,8]. Unfortunately, various industrial chemicals containing phenolic groups can disrupt physiological responses to the ER in healthy people, and thus act as endocrine disruptors (Fig. 4) [[8], [9], [10], [11], [12]]. Interestingly, many natural products in plants also contain phenolic structures which yield phytochemicals that are transcriptional activators of the ER (Fig. 5) [8,9,[13], [14], [15]]. The diversity in the A ring of physiological estrogens (Fig. 1) also expands the potential structures of chemicals that can be used as drugs for treating estrogen-dependent diseases in vertebrates, as well as of industrial chemicals that need to be screened for potential disruption of estrogen physiology [9,16]. Synthesis of 27-hydroxycholesterol and Δ5-androstenediol is simpler than that of E2 [4,9,17] (Fig. 6), and this has important implications for the identity of the estrogen-like molecule that was the transcriptional activator the ancestral ER [9,[18], [19], [20]]. The earliest ortholog of mammalian ER is found in amphioxus [4,17,[21], [22], [23]], a marine chordate that diverged from vertebrates more than 520 million years ago. Based on parsimony, we propose that one or both of these C19-containing steroids or a related metabolite were ligands for the early chordate ER, with E2 evolving later as the canonical estrogen [9,18]. Many actions of the ER in non-reproductive tissues evolved in vertebrates long before the evolution of mammals, in which reproductive activity of the ER has long been a main focus [24,25]. An evolutionary perspective of ER signaling [9,26] provides insights into its promiscuous actions in different tissues: brain, heart, bone, and kidney, as well as traditional ER activities in reproductive organs.
    Estradiol, a hormone with many physiological actions in females and males Owing to its key role in female reproduction, E2 often is described as a ‘female’ sex hormone. However, E2 also is an important steroid in males [27,28]. The physiological actions of E2 and other estrogens are mediated by two ER isoforms, ERα and ERβ [[29], [30], [31]]. Through transcriptional activation of these ERs, estrogens regulate a variety physiological responses in reproductive organs [24,25,28,30], brain [[32], [33], [34], [35]], bone, and the cardiovascular system [24].
    What is an estrogen? E2 is the major physiological ligand for the vertebrate ERs [25,30]. Compared to other adrenal and sex steroids, E2 is a compact hydrophobic molecule with few side chains that could interact with the ER (Fig. 2). The aromatic A ring on E2 is unique among adrenal and sex steroids (Fig. 2). The crystal structures of ERα and ERβ provide insights into the key contacts between E2 and the ER [8,36,37]. Owing to Molidustat the aromatic chemistry in the A ring, the C3-alcohol can function as a hydrogen-bond donor and acceptor with Arg-394 and Glu-353 in human ERα [8,36] (Fig. 7) and with Arg-346 and Glu-305 in ERβ [37] (Supplement Fig. S1). In addition, because of the aromatic A ring, the interface between the A and B ring is flat and E2 lacks a C19 methyl group, which allows ERα and ERβ to form a close contact with this part of E2 (Figs. 7, S1) [8,16,36,37]. By contrast, testosterone and other 3-ketosteroids (Fig. 2) have a different A ring and contain a C19 methyl group, and thus their receptors use a different chemistry to contact the A ring [[38], [39], [40], [41]].