Abstract
AbstractIn the last decade, there has been important progress in understanding the origins and evolution of receptors for adrenal steroids (aldosterone, cortisol) and sex steroids (estradiol, progesterone, testosterone) due to the sequencing of genomes from animals that are at key sites in vertebrate evolution. Although the estrogen receptor [ER] appears to be the ancestral vertebrate steroid receptor and estradiol [E2] is the physiological ligand for vertebrate ERs, the identity of the ancestral ligand(s) for the ER remains unknown. Here, using an analysis of crystal structures of human ER[alpha] with E2 and other chemicals and 3D models of human ER[alpha] with 27-hydroxycholesterol and 5-androsten-3[beta],17[beta]-diol, we propose that one or more [DELTA]5 steroids were the ancestral ligands for the ER, with E2 evolving later as the canonical estrogen. The evidence that chemicals with a [beta]-hydroxy at C3 in a saturated A ring can act as estrogens and the conformational flexibility of the vertebrate ER can explain the diversity of synthetic chemicals that disrupt estrogen responses by binding to vertebrate ERs.
Highlights
The adrenal steroids, aldosterone and cortisol, and sex steroids, estradiol (E2), progesterone and testosterone, regulate a wide range of physiological processes including reproduction, development and homeostasis [Figure 1]
The physiological actions of these vertebrate steroids are mediated by nuclear receptors, a large and diverse group of transcription factors that arose in multicellular animals [1,2,3,4]
Nuclear receptors with transcriptional responses to adrenal and sex steroids appear to have evolved in deuterostomes [5,6,7]; the estrogen receptor [ER] is the ancestral vertebrate steroid receptor [6,7,8,9,10,11]
Summary
The adrenal steroids, aldosterone and cortisol, and sex steroids, estradiol (E2), progesterone and testosterone, regulate a wide range of physiological processes including reproduction, development and homeostasis [Figure 1]. A problem with having the ER as the ancestral receptor is that estradiol [E2], the physiological ligand for vertebrate ERs, is at the end of the pathway for the synthesis of steroids from cholesterol [7, 22] [Figure 2].
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