Vitamin D metabolism (Homo sapiens)

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6VDR targets Skin5Vitamin D from DietUV B radiation from sunlightEndocrine modulatorsSpontaneous isomerisationLegend:CholecalciferolVDRPrevitamin D3CYP27A1RXRB7-Dehydro-cholesterolDHCR7CalcitriolCalcidiolCYP2R1 CYP24A1Vitamin D binding proteinPialpha-globulinInactive24,25-OH-vitamin DCholesterolCaCalcidiolParathyroid hormoneRXRAVitamin D binding proteinCYP27B12, 3, 84Activation7Tissue-specific regulationHepatocyteKidney


Description

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 CPTAC Assay Portal.

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Bibliography

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  1. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton SM, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC; ''A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution.''; Genome Res, 2010 PubMed Europe PMC Scholia
  2. Norman AW; ''From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health.''; Am J Clin Nutr, 2008 PubMed Europe PMC Scholia
  3. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW; ''Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase.''; Proc Natl Acad Sci U S A, 2004 PubMed Europe PMC Scholia
  4. Waterham HR, Wanders RJ; ''Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome.''; Biochim Biophys Acta, 2000 PubMed Europe PMC Scholia
  5. Ahn J, Yu K, Stolzenberg-Solomon R, Simon KC, McCullough ML, Gallicchio L, Jacobs EJ, Ascherio A, Helzlsouer K, Jacobs KB, Li Q, Weinstein SJ, Purdue M, Virtamo J, Horst R, Wheeler W, Chanock S, Hunter DJ, Hayes RB, Kraft P, Albanes D; ''Genome-wide association study of circulating vitamin D levels.''; Hum Mol Genet. 2010 Jul 1;19(13):2739-45, 2010 PubMed Europe PMC Scholia
  6. Guo YD, Strugnell S, Back DW, Jones G; ''Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions.''; Proc Natl Acad Sci U S A, 1993 PubMed Europe PMC Scholia
  7. Thomas J Wang*, Feng Zhang*, J Brent Richards*, Bryan Kestenbaum*, Joyce B van Meurs*, Diane Berry*, Douglas P Kiel, Elizabeth A Streeten,

    Claes Ohlsson, Daniel L Koller, Leena Peltonen†, Jason D Cooper, Paul F O’Reilly, Denise K Houston, Nicole L Glazer, Liesbeth Vandenput, Munro Peacock, Julia Shi, Fernando Rivadeneira, Mark I McCarthy, Pouta Anneli, Ian H de Boer, Massimo Mangino, Bernet Kato, Deborah J Smyth, Sarah L Booth, Paul F Jacques, Greg L Burke, Mark Goodarzi, Ching-Lung Cheung, Myles Wolf, Kenneth Rice, David Goltzman, Nick Hidiroglou, Martin Ladouceur, Nicholas J Wareham, Lynne J Hocking, Deborah Hart, Nigel K Arden, Cyrus Cooper, Suneil Malik, William D Fraser, Anna-Liisa Hartikainen, Guangju Zhai, Helen M Macdonald, Nita G Forouhi, Ruth J F Loos, David M Reid, Alan Hakim, Elaine Dennison, Yongmei Liu, Chris Power, Helen E Stevens, Laitinen Jaana, Ramachandran S Vasan, Nicole Soranzo, Jörg Bojunga, Bruce M Psaty, Mattias Lorentzon, Tatiana Foroud, Tamara B Harris, Albert Hofman, John-Olov Jansson, Jane A Cauley, Andre G Uitterlinden, Quince Gibson, Marjo-Riitta Järvelin, David Karasik,

    David S Siscovick, Michael J Econs, Stephen B Kritchevsky, Jose C Florez, John A Todd*, Josee Dupuis*, Elina Hyppönen*, Timothy D Spector*; ''Common genetic determinants of vitamin D insufficiency: a genome-wide association study''; Lancet,376:180-188, 2010 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
128578view04:31, 14 February 2024EweitzFix site-PathVisio discrepancy in text width, distinguish process via color, use gene symbol
128573view14:00, 13 February 2024EweitzRefine metabolite placement
128572view13:59, 13 February 2024EweitzRefine cell label graphics to mitigate site rendering bug
128571view13:54, 13 February 2024EweitzEconomize layout
128570view13:19, 13 February 2024EweitzEconomize layout
128569view04:57, 13 February 2024EweitzStandardize font, economize layout, refine legend, standardize case
118354view13:32, 27 May 2021Mkutmonfix publication ref
117856view15:20, 22 May 2021EweitzModified title
107120view14:19, 17 September 2019MaintBotChEBI identifier normalization
106185view12:08, 16 August 2019MaintBotHMDB identifier normalization
105853view23:17, 15 August 2019KhanspersModified description
104243view15:25, 11 May 2019EgonwRemoved the RHEA: prefix from the identifier.
103420view09:22, 28 February 2019DeSlAdded rhea to reaction from 7-DH-cholesterol to cholesterol+MIM-modification to MIM-conversion; changed ID for previtamin D3 from HMDb to ChEBI; changed MIMconversion to MImmodification for reaction with sunlight.
101956view09:20, 21 November 2018DeSlChanged layout for readability.
101955view09:08, 21 November 2018DeSlRemoved licence number
96858view23:32, 14 April 2018AlexanderPicoReverted to version '19:53, 15 September 2015' by AlexanderPico
96825view00:37, 11 April 2018Artoria2e5Modified description
96824view00:36, 11 April 2018Artoria2e5Modified description
82221view02:53, 16 September 2015AlexanderPicofixing arrowheads for biopax conversion
74057view10:23, 26 March 2014Mkutmonfixed unconnected lines, layout
73558view22:18, 31 January 2014MaintBotremoves comments
71552view19:26, 17 October 2013MaintBotUpdated data sources
70322view10:11, 17 July 2013EveloModified title
70034view01:59, 12 July 2013AlexanderPicoModified title
69840view15:25, 11 July 2013EveloOntology Term : 'osteomalacia' added !
68004view06:19, 29 June 2013EgonwMarked the VitD-binding protein as Protein (hoping that will fix the link to Uniprot/TrEMBL)
67745view11:57, 26 June 2013DdiglesOntology Term : 'vitamin D metabolic pathway' added !
46487view10:03, 2 February 2012LribeiroPeriodical save, work in progress
46379view00:36, 24 January 2012KhanspersOntology Term : 'kidney cell' added !
46378view00:35, 24 January 2012KhanspersOntology Term : 'hepatocyte' added !
46377view00:35, 24 January 2012KhanspersOntology Term : 'skin fibroblast' added !
46376view00:26, 24 January 2012KhanspersAdded xrefs, connected lines, changed graphical style
45011view17:49, 6 October 2011KhanspersOntology Term : 'rickets' added !
45010view17:45, 6 October 2011KhanspersOntology Term : 'metabolic pathway of cofactors and vitamins' added !
42790view12:53, 30 April 2011LribeiroPeriodical save, work in progress
42789view12:34, 30 April 2011LribeiroPeriodical save, work in progress
42788view12:24, 30 April 2011LribeiroPeriodical save, work in progress
42787view12:03, 30 April 2011LribeiroPeriodical save, work in progress
42786view11:24, 30 April 2011LribeiroPeriodical save, work in progress
42785view11:14, 30 April 2011LribeiroPeriodical save, work in progress
42784view11:04, 30 April 2011LribeiroPeriodical save, work in progress
42778view19:31, 29 April 2011LribeiroPeriodical save, work in progress
42777view19:20, 29 April 2011LribeiroModified description
42776view19:16, 29 April 2011LribeiroPeriodical save, work in progress
42775view19:03, 29 April 2011LribeiroPeriodical save, work in progress
42774view18:53, 29 April 2011LribeiroPeriodical save, work in progress
42773view18:42, 29 April 2011LribeiroPeriodical save, work in progress
41192view23:43, 1 March 2011MaintBotRemoved redundant pathway information and comments
38456view18:18, 14 September 2010KhanspersChanged spacing and layout
38455view18:17, 14 September 2010KhanspersPeriodical save, work in progress

External references

DataNodes

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NameTypeDatabase referenceComment
7-Dehydro- cholesterolMetaboliteHMDB0000032 (HMDB)
CYP24A1GeneProduct1591 (Entrez Gene)
CYP27A1GeneProduct1593 (Entrez Gene)
CYP27B1GeneProduct1594 (Entrez Gene)
CYP2R1 GeneProduct120227 (Entrez Gene)
CaMetaboliteHMDB0000464 (HMDB)
CalcidiolMetaboliteHMDB0003550 (HMDB)
CalcitriolMetaboliteHMDB0001903 (HMDB)
CholecalciferolMetaboliteHMDB0000876 (HMDB)
CholesterolMetaboliteHMDB0000067 (HMDB)
DHCR7GeneProduct1717 (Entrez Gene)
Inactive

24,25-OH-

vitamin D		MetaboliteHMDB0000430 (HMDB)
Parathyroid hormoneGeneProduct5741 (Entrez Gene)
PiMetaboliteHMDB0001429 (HMDB)
Previtamin D3Metabolite8403 (ChEBI)
RXRAGeneProduct6256 (Entrez Gene)
RXRBGeneProduct6257 (Entrez Gene)
VDRGeneProduct7421 (Entrez Gene)
Vitamin D binding proteinGeneProduct2638 (Entrez Gene)
Vitamin D binding proteinProteinP02774 (Uniprot-TrEMBL)
alpha-globulinGeneProduct

Annotated Interactions

SourceTargetTypeDatabase referenceComment
7-Dehydro- cholesterolCholesterolmim-conversion23986 (Rhea)
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