Vitamin D metabolism (WP1531)

Homo sapiens

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Photochemical synthesis of vitamin D3 (cholecalciferol, D3) occurs cutaneously where pro-vitamin D3 (7-dehydrocholesterol) is converted to pre-vitamin D3 (pre-D3) in response to ultraviolet B (sunlight) exposure. DHCR7 encodes the enzyme 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, thereby removing the substrate from the synthetic pathway of vitamin D3, a precursor of 25-hydroxyvitamin D3.The finding that common variants at DHCR7 are strongly associated with circulating 25-hydroxyvitamin D concentrations suggests that this enzyme could have a larger role in regulation of vitamin D status than has previously been recognised. Vitamin D3, obtained from the isomerization of pre-vitamin D3 in the epidermal basal layers or intestinal absorption of natural and fortified foods and supplements, binds to vitamin D-binding protein (DBP) in the bloodstream, and is transported to the liver. D3 is hydroxylated by liver 25-hydroxylases (25-OHase). The resultant 25-hydroxycholecalciferol (25(OH)D3) is 1-hydroxylated in the kidney by 25-hydroxyvitamin D3-1 -hydroxylase (1-OHase). This yields the active secosteroid 1 ,25(OH)2D3 (calcitriol), which has different effects on various target tissues. The synthesis of 1,25(OH)2D3 from 25(OH)D3 is stimulated by parathyroid hormone (PTH) and suppressed by Ca2+, Pi and 1,25(OH)2D3 itself. The rate-limiting step in catabolism is the degradation of 25(OH)D3 and 1,25(OH)2D3 to 24,25(OH)D3 and 1,24,25(OH)2D3, respectively,which occurs through 24-hydroxylation by 25-hydroxyvitamin D 24-hydroxylase (24-OHase), encoded by the CYP24A1 gene. 24,25(OH)D3 and 1,24,25(OH)2D3 are consequently excreted. Vitamin D activity is mediated through binding of 1,25(OH)2D3 to the vitamin D receptor (VDR), which can regulate transcription of other genes involved in cell regulation, growth, and immunity. VDR modulates the expression of genes by forming a heterodimer complex with retinoid-X-receptors (RXR). Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP1531 CPTAC Assay Portal].

Authors

Chris Evelo , Lucia Ribeiro , Kristina Hanspers , Alex Pico , Martijn Van Iersel , Daniela Digles , Egon Willighagen , Martina Summer-Kutmon , Mingye Wang , Denise Slenter , and Eric Weitz

Activity

last edited

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Cited In

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Organisms

Homo sapiens

Communities

Micronutrients Renal Genomics Pathways

Annotations

Cell Type Ontology

kidney cell skin fibroblast hepatocyte

Disease Ontology

rickets osteomalacia

Pathway Ontology

metabolic pathway of cofactors, vitamins, nutrients vitamin D metabolic pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
Inactive24,25-OH-vitamin D Metabolite hmdb:HMDB0000430
Calcidiol Metabolite hmdb:HMDB0003550
Previtamin D3 Metabolite chebi:8403
Calcitriol Metabolite hmdb:HMDB0001903
Pi Metabolite hmdb:HMDB0001429
Cholecalciferol Metabolite hmdb:HMDB0000876
Cholesterol Metabolite hmdb:HMDB0000067
7-Dehydro-cholesterol Metabolite hmdb:HMDB0000032
Ca Metabolite hmdb:HMDB0000464
RXRA GeneProduct ncbigene:6256
PTH GeneProduct ncbigene:5741
CYP2R1 GeneProduct ncbigene:120227
DHCR7 GeneProduct ncbigene:1717
CYP27A1 GeneProduct ncbigene:1593
Vitamin D binding protein GeneProduct ncbigene:2638
Alpha globulin GeneProduct :https://www.wikidata.org/wiki/Q2440935
RXRB GeneProduct ncbigene:6257
VDR GeneProduct ncbigene:7421
CYP24A1 GeneProduct ncbigene:1591
CYP27B1 GeneProduct ncbigene:1594
Vitamin D binding protein Protein uniprot:P02774

References

  1. Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions. Guo YD, Strugnell S, Back DW, Jones G. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8668–72. PubMed Europe PMC Scholia
  2. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Waterham HR, Wanders RJ. Biochim Biophys Acta. 2000 Dec 15;1529(1–3):340–56. PubMed Europe PMC Scholia
  3. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7711–5. PubMed Europe PMC Scholia
  4. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Norman AW. Am J Clin Nutr. 2008 Aug;88(2):491S-499S. PubMed Europe PMC Scholia
  5. Genome-wide association study of circulating vitamin D levels. Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, et al. Hum Mol Genet. 2010 Jul 1;19(13):2739–45. PubMed Europe PMC Scholia
  6. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, et al. Lancet. 2010 Jul 17;376(9736):180–8. PubMed Europe PMC Scholia
  7. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, et al. Genome Res. 2010 Oct;20(10):1352–60. PubMed Europe PMC Scholia