Estradiol is an important estrogen steroid hormone in both women and men. It is a typical steroid with core four-ring system (ABCD), composed of 17 carbon atoms. Cutting Ring B produces secosteroids one of which is vitamin D3. 25-hydroxy-cholecalciferol (25-D3); 25-hydroxyvitamin D3 (5ien). Calcitriol is the active form of vitamin D pro-hormone.
Types by function
Cortisol, a glucocorticoid whose functions include immunosuppression
Aldosterone, a mineralocorticoid which helps regulate blood pressure through water and electrolyte balance
Sex steroids
Progesterone, which regulates cyclical changes in the endometrium of the uterus and maintains a pregnancy
Testosterone, which contributes to the development and maintenance of male secondary sex characteristics
Estradiol, which contributes to the development and maintenance of female secondary sex characteristics
Additional classes of steroids:
Neurosteroids such as DHEA and allopregnanolone
Aminosteroid neuromuscular blocking agents such as pancuronium bromide
Vitamin D forms such as ergocalciferol, cholecalciferol, and calcitriol.
Vitamin D.
25-hydroxy-cholecalciferol (25-D3); 25-hydroxyvitamin D3 (5ien)
Calcitriol is the active form of vitamin D pro-hormone.
Vitamin D receptor (VDR) is a transcription factor. Upon binding to vitamin D, VDR forms a heterodimer with retinoid-X receptor and binds to hormone response receptors on DNA causing gene expression. The vitamin D hormone (green) binds to receptors in its target cells, controlling the synthesis of many different proteins involved in Ca transport and utilization.
Vitamin D hormone binding site.
Vitamin D hormone is located in deep pocket. VDR contains 2 domains: a ligand binding domain (LBD), that binds to the hormone (grey) and DNA-binding domain (DBD) that binds to DNA (green and blue are 2 same VDR structures). It pairs up with a similar protein, 9-cis retinoic acid receptor (RXR), and together they bind to the DNA, activating synthesis in some cases and repressing it in others. When serine is mutated it is replaced with a glycine which results in an inhibition of transcriptional activation. When transcription is inhibited it results in p53 accumulation, which activates and promotes p53 translocation into mitochondria leading to apoptosis. Serine is replaced with aspartic acid when mutated creating a negative charge. The negative charge at the residue inhibits DNA binding which cause a downregulation of VDR activity. VDR needs DNA binding in order for it to be activated which is only possible with a serine residue.
The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 α,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. It was shown that the synthetic analogue (20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D(3) (2a) acts as a 1α,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1α,25(OH)(2)D(3), 2α-methyl-1α,25(OH)(2)D(3), or 2a, a novel analogue, 2α-methyl-(20S,23S)-epoxymethano-1α,25-dihydroxyvitamin D(3) (4a) was designed, in order to increase its transactivation potency.
