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.
Highlights
1α,25-Dihydroxyvitamin D3 (1,25D3, calcitriol, Figure 1) is the most active metabolite of vitamin D
Many of the immune cell types express the receptor for vitamin D (VDR): 1,25D3 has an important role in their function and is, important to good health [5,6]
Our new PRI-1916 and PRI-1917 showed a somewhat lower resistance to conversion, still higher than that of 1,25D3 and 1,25D2. From these findings we proved that a rigid and straight (24E) geometry of the side-chain is preferred for metabolic resistance, and in keeping (24E), (24-trans) analogues elicit long-term biological effects against cancer cells [25]. (24Z) Modification of the side-chain of 1,25D2 analogues has a contrasting effect on the differentiating activity of PRI-1906 and PRI-1907
Summary
1α,25-Dihydroxyvitamin D3 (1,25D3, calcitriol, Figure 1) is the most active metabolite of vitamin D (vitD, cholecalciferol). This seco-steroid hormone has many biological roles [1]. 1,25D3 plays a key role in decision-making by cells because it can elicit events that result in many types of cells arresting their growth, differentiating, and undergoing apoptosis. The anti-proliferative action of 1,25D3 extends to malignant cells, leading to interest in its use for differentiation therapy of leukemia and other cancers. Many of the immune cell types express the receptor for vitamin D (VDR): 1,25D3 has an important role in their function and is, important to good health [5,6].
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