1[alpha],25

• Published in: PloS one 2011-03, Vol.6 (3), p.e18124
• Main Authors: Molnár, Ferdinand, Sigüeiro, Rita, Sato, Yoshiteru, Araujo, Clarisse, Schuster, Inge, Antony, Pierre, Peluso, Jean, Muller, Christian, Mouriño, Antonio, Moras, Dino, Rochel, Natacha
• Format: Article
• Language: English
• Subjects: Comparative analysis; Crystal structure; Hydrogen; Metabolites; Physiological aspects; Vitamin D
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0018124

The 1[alpha],25-dihydroxy-3-epi-vitamin-D.sub.3 (1[alpha],25(OH).sub.2 -3-epi-D.sub.3 ), a natural metabolite of the seco-steroid vitamin D.sub.3, exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1[alpha],25(OH).sub.2 -3-epi-D.sub.3 is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1[alpha],25(OH).sub.2 D.sub.3 . To further unveil the structural mechanism and structure-activity relationships of 1[alpha],25(OH).sub.2 -3-epi-D.sub.3 and its receptor complex, we characterized some of its in vitro biological properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD). In the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1[alpha],25(OH).sub.2 D.sub.3 . We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the number of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addition, the biological activity of the 1[alpha],25(OH).sub.2 -3-epi-D.sub.3 in primary human keratinocytes and biochemical properties are comparable to 1[alpha],25(OH).sub.2 D.sub.3. The physiological role of this pathway as the specific biological action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biologic activity makes this natural metabolite an interesting ligand for clinical applications. Our new findings contribute to a better understanding at molecular level how natural metabolites of 1[alpha],25(OH).sub.2 D.sub.3 lead to significant activity in biological systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochemical and biological properties to those of the 1[alpha],25(OH).sub.2 D.sub.3.