Vitamin D and in particular its biologically most active metabolite, 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), are central endocrine molecules that influence many aspects of human physiology, which are not only the well-known calcium and phosphorus up-take and transport controlling bone formation, but also the control of immune functions and of cellular growth and differentiation. Basically all actions of 1α,25(OH)2D3 are mediated by the transcription factor vitamin D receptor (VDR). The crystal structure of the VDR and detailed knowledge on its molecular interactions with the ligand provide significant insight into the mechanisms of vitamin D signaling. This applies also on the action of the huge number of synthetic 1α,25(OH)2D3 analogues, which have been developed with the goal of a therapeutic application in hyper-proliferative diseases, such as psoriasis, benign prostate hyperplasia and different types of cancer, in immune functions, such as autoimmune diseases and microbial infections, or in bone disorders, such as osteoporosis. Moreover, detailed investigations on many VDR target genes and in particular the recently available genome-wide view on vitamin D signaling allows a more complete view on the potential of the nuclear hormone. In this review we discuss the latest insight into vitamin D signaling in context with the most prominent 1α,25(OH)2D3 analogues.

The 1α,25-dihydroxy-3-epi-vitamin-D₃ (1α,25(OH)₂-3-epi-D₃), a natural metabolite of the seco-steroid vitamin D₃, exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1α,25(OH)₂-3-epi-D₃ is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1α,25(OH)₂D₃. To further unveil the structural mechanism and structure-activity relationships of 1α,25(OH)₂-3-epi-D₃ 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 1α,25(OH)₂D₃. 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 1α,25(OH)₂-3-epi-D₃ in primary human keratinocytes and biochemical properties are comparable to 1α,25(OH)₂D₃. 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 1α,25(OH)₂D₃ 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 1α,25(OH)₂D₃.

Introduction: Vitamin D₃ activates via its hormonal form 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃), the transcription factor vitamin D receptor (VDR). VDR is expressed in most human tissues and has more than 1,000 target genes. Thus, 1α,25(OH)₂D₃ and its synthetic analogs have a broad physiological impact. The crystal structures of the VDR ligand-binding domain (LBD), and its various ligands, allows further the understanding of the receptor’s molecular actions. Areas covered: We discuss the most important novel VDR ligands and the further insight derived from new structural information on VDR. Expert opinion: There is an increasing appreciation of the impact of vitamin D and its receptor VDR not only in bone biology, but also for metabolic diseases, immunological disorders, and cancer. Detailed structural analysis of the interaction of additional novel ligands with VDR highlight helices 6 and 7 of the LBD as being most critical for stabilizing the receptor for an efficient interaction with co-activator proteins, i.e. for efficient agonistic action. This permits the design of even more effective VDR agonists. In addition, chemists took more liberty in replacing major parts of the 1α,25(OH)₂D₃ molecule, such as the A- and CD-rings or the side chain, with significantly different structures, such as carboranes, and still obtained functional VDR agonists.

Vitamin D, obtained from diet or synthesized internally as cholecalciferol and ergocalciferol, influences bodily functions through its most active metabolite and the vitamin D receptor. Recent research has uncovered multiple roles for vitamin D in the central nervous system, impacting neural development and maturation, regulating the dopaminergic system, and controlling the synthesis of neural growth factors. This review thoroughly examines these connections and investigates the consequences of vitamin D deficiency in neurological disorders, particularly neurodegenerative diseases. The potential benefits of vitamin D supplementation in alleviating symptoms of these diseases are evaluated alongside a discussion of the controversial findings from previous intervention studies. The importance of interpreting these results cautiously is emphasised. Furthermore, the article proposes that additional randomised and well-designed trials are essential for gaining a deeper understanding of the potential therapeutic advantages of vitamin D supplementation for neurological disorders. Ultimately, this review highlights the critical role of vitamin D in neurological well-being and highlights the need for further research to enhance our understanding of its function in the brain.