Vitamins D: Relationship between Structure and Biological Activity

Abstract

The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D3 regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D3 that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D3 that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D3, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D3: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D3- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair β-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D.

Targeting Vitamin D Deficiency to Limit Exacerbations in Respiratory Diseases: Utopia or Strategy With Potential?

“…The direct, well-controlled, and fast actions of vitamin D in the context of calcium homeostasis have been extensively described elsewhere [15]. 1,25(OH) 2 D also exerts genomic actions by regulating gene transcription true binding to a nuclear Vitamin D receptor (VDR) and forming a heterodimer with the retinoid X receptor (RXR), regulating in this way 3% of the human genome [13,16,17]. As such, vitamin D regulates genes that are linked to diverse biological processes such as cell proliferation and differentiation, cell control, apoptosis, and angiogenesis [18].…”

Chondroprotection and Molecular Mechanism of Action of Phytonutraceuticals on Osteoarthritis

“…Increased vitamin C intake, an antioxidant vitamin found in many fruits and vegetables, reduces cartilage loss and the risk of OA progression in patients with this condition. While vitamin D 3 is a central regulator of mineral homeostasis [ 21 ]. Thus, understanding the effect of vitamin deficiency on joint health and the importance of nutritional supplements for OA prevention or treatment is of significant scientific and clinical interest.…”

Allergy Modulation by N-3 Long Chain Polyunsaturated Fatty Acids and Fat Soluble Nutrients of the Mediterranean Diet

“…1,25(OH)2D3 binds to the Vitamin D receptor (VDR), a member of the nuclear receptor superfamily ( Kutner and Brown, 2018 ). VDR heterodimerizes with nuclear receptors of the RXR family after binding to 1,25(OH)2D3, allowing the VDR-RXR heterodimer to bind Vitamin D Responsive Elements (VDREs) ( Kutner and Brown, 2018 ). Depending on the target gene, this induces or represses gene transcription ( Baeke et al, 2010 ; Haussler et al, 2011 ).…”