1. Vitamin D: Synthesis and Its Relationship to Calcium Intake Presented by: Tuan Le

2. Outline 1. Introduction to Vitamin D  What is Vitamin D  Formula and name 2.IR analysis 3.Synthesis of Vitamin D  Step 1 in skin  Step 2 in liver  Step 3 in kidney 4.Vitamin D receptor  Structure  Mechanism 5. The role of vitamin D in calcium absorption 6. Future prospects  Basic research  Clinical application 6.Conclusion

3. Introduction to vitamin D Vitamin D3, known as cholecalciferol, is the natural humnan form of vitamin D Vitamin D is a steroid hormone which plays an important role in regulating body levels of calcium and mineralization of bone Receptors for vitamin D are present in a wide variety of cells, and that this hormone has biologic effects which extend far beyond control of mineral metabolism. Structure of cholecalciferol:

4. IR analysis of Vitamin D3 OH Alkanes Aromatic C-H C=C

5. Synthesis of Vitamin D Step 1: In skin Vitamin D3, also known as cholecalciferol is generated in the skin when light energy is absorbed by a precursor molecule 7-dehydrocholesterol http://en.wikipedia.org/wiki/Vitamin_D

6. Synthesis of Vitamin D (cont.) Step 2: In liver Cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by the enzyme 25- hydroxylase. This is a antarafacial hydride [1,7]Sigmatropic shift http://en.wikipedia.org/wiki/Vitamin_D

7. Synthesis of Vitamin D (cont.) Step 3: In kidney 25-vitamin D serves as a substrate for 1-alpha-hydroxylase, yielding 1,25- dihydroxycholecalciferol, the biologically active form of vitamin D http://en.wikipedia.org/wiki/Vitamin_D

8. Structure of Vitamin D receptor VDR domains are defined as the N-terminal A/B domain, region C or the DNA-binding domain (DBD), the hinge region, and the multifunctional ligand-binding domain (LBD) (http://www.bioscience.org/1998/V3/d/kraichel/3.htm)

9. Mechanism of VDR to regulate gene expression (step 1) 1,25(OH)2D-initiated gene transcription as it enters the target cell and binds to its receptor, VDR

10. Mechanism of VDR to regulate gene expression (step 2) The VDR then heterodimerizes with the retinoid X receptor (RXR). This increases the affinity of the VDR/RXR complex for the vitamin D response element (VDRE) Binding of the VDR/RXR complex to the VDRE attracts a complex of proteins termed coactivators to the VDR/RXR complex. The coactivator complex spans the gap between the VDRE and RNA polymerase II and other proteins in the initiation complex centered at or around the TATA box (or other transcription regulatory elements)

11. Mechanism of VDR to regulate gene expression (step 3) Transcription of the gene is initiated to produce the corresponding mRNA, which leaves the nucleus to be translated to the corresponding protein.

12. Calcium Homeostasis http://lpi.oregonstate.edu/infocenter/minerals/phosphorus/phospth.html

13. Role of vitamin D in Calcium Homeostasis Calcium receptor of parathyroid gland senses the calcium level in blood Low blood calcium causes the release of parathyroid hormone (PTH) PTH stimulates the activity of the 1-hydroxylase enzyme in the kidney, resulting in increased production of calcitriol Increased calcitriol production restores normal serum calcium levels in three different ways: 1) By activating the vitamin D-dependent transport system in the small intestine, increasing the absorption of dietary calcium 2) By increasing the mobilization of calcium from bone into the circulation 3) By increasing the reabsorption of calcium by the kidneys

14. Future prospects I. Basic research  Further research on structure function analysis of vitamin D endocrine system. Current area of active investigations include bone cell biology and hematopoiesis, effects of vitamin D on phosphate transport, and action in immune system II. Clinical application:  Drugs for diseases known to be caused by abnormalities in vitamin D homeostasis  Skin diseases such as psoriasis  Drugs are being developed for immune depression and modulation because

15. Conclusion I.Summary about the presentation:  Short introduction about name and formula of vitamin D  IR analysis  Synthesis of vitamin D in skin, liver and kidney  Vitamin D receptor and its mechanism to regulate gene expression  The role of vitamin D in calcium absorption  Future prospects II. Source of vitamin D:  Food such as milk, salmons, tunas, sardines and some kind of cereals  Sun exposure is very important source of vitamin D for human

16. References Brown, Alex, Adriana Dusso, and Eduardo Slatopolsky. “Vitamin D.” Am J Physiol Renal Physiol Aug. 1999; 277: 157 - 175 Kraichely, Dennis, and Paul McDonald. “ Transcriptional Activation Through The Vitamin D Receptor in Osteoblasts. Frontiers in Bioscience 6 May. 1998. 28 April 2006 Bikle, Dianel. “Vitamin D: Production, Metabolism, and Mechanisms of Action.” 10 Jan. 2006. 28 April 2006 “Vitamin D (Cholecalciferol, Calcitriol)” Colorado State University. 9 August 2001. 28 April 2006 “Vitamin D.” Wikipedia. 28 April. 2006. 28 April 2006 http://www.aist.go.jp/RIODB/SDBS/cgi-bin/cre_index.cgi?lang=eng