Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Abstract

Abstract. Receptors for the adrenal and sex steroids arose by a series of gene duplications from an ancestral nuclear receptor in a primitive vertebrate, at least 540 million years ago. Sequence analysis indicates many steroidogenic and steroid-inactivating enzymes, including cytochrome P450s and hydroxysteroid dehydrogenases, arose at the same time. The estrogen receptor (ER) appears to be the ancestral steroid receptor. Initially, the redundant duplicated ER had a low specificity for its new ligand. This raises the question: "How was specificity for responses to different steroids regulated early in the evolution of steroid receptors?" Selective expression of these steroid-metabolizing enzymes provided specificity for different steroid responses in primitive vertebrates. 17 -hydroxysteroid dehydrogenase-type 1 (17 -HSD-type 1) and 17 -HSD-type 2, which preferentially catalyze the reduction and oxidation at C17 of androgens and estrogens, respectively, provide an example of this mechanism. Selective expression of either 17 -HSD-type 1 or 17 -HSD-type 2 can regulate synthesis or inactivation of androgens or estrogens in specific cells.Steroids also were important in the evolution of land animals, which began about 400 million years ago.Steroidogenic and steroid-inactivating enzymes were recruited to regulate steroid-mediated responses as organ function became more complex. For example, in the kidney 11 -HSD-type 2 prevents binding of glucocorticoids to the mineralocorticoid receptor, which is crucial for aldosterone-mediated regulation of electrolyte transport in the distal tubule. We propose that 5 steroids, such as dehydroepiandrosterone and its metabolites, were the ligands for the ancestral ER. Understanding the actions of 5 steroids in amphioxus and lamprey may shed light on adrenarche and neurosteroid actions in humans.

Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

“…In an alternative model, 5-androsten-3 ,17 -diol [ 5 -androstenediol], which is upstream of E2, has been proposed as a ligand for the ancestral ER [22][23] [ Figure 3]. Here, we provide support for this latter hypothesis, using data from crystal structures of human ER with E2 and other steroids and 3D models of human ER with 5 steroids.…”

“…However, steroids that lack an aromatic A ring and contain a 3 -hydroxyl group, such as 5 -androstenediol and 5 -androstane-3 ,17 -diol [3 -Adiol] also have high affinity for the mammalian ER [30] and could have served as ligands for the ancestral ER [22][23]. Indeed, 3 -Adiol is an active estrogen in the prostate [35], as well as in the brain, under conditions in which E2 is not present [36].…”

“…Thus, either steroid could have been an active estrogen before the evolution of CYP19. Moreover, 5 -androstenediol could have been an active estrogen before the evolution of 3 / 5-4 -HSD [22][23].…”

3D model of amphioxus steroid receptor complexed with estradiol

“…However, physiological regulation of amphioxus SR activity by 100 nM E2 is unlikely because the E2 concentration in amphioxus is low [34]. It may be that the SR is activated by an estradiol derivative [19,20]or other steroids, such as Δ5-androstene-3β,17β-diol [Δ5-Adiol] and 5-androstane-3β,17β-diol [17,21]. Both Δ5-Adiol and 5-androstane-3β,17β-diol have Kds in the nM range for human ERα [15], and both steroids contain a C3 alcohol and a 17β-hydroxyl that can form a hydrogen bond with Glu-346 and His-506, respectively, in amphioxus SR. Δ5-Adiol, which is formed from DHEA by reduction of the C17-ketone to an alcohol can be metabolized to testosterone by 3β-hydroxysteroid dehydrogenase.…”

“…However, other interactions between estradiol and human ERα are not conserved in amphioxus SR, which can explain the lower response to E2 of the SR compared to human ERα. These differences in the steroid-binding site of amphioxous SR may mean that novel estradiol derivatives [19,20] or other steroids [17,21] are the physiological ligands for amphioxus SR. Our 3D model of amphioxus SR predicts that mutation of Glu-346 to Gln will increase the affinity of testosterone for amphioxus SR and elucidate the evolution of steroid binding to nuclear receptors.…”