CYP2R1

Vitamin D 25-hydroxylase also known as cytochrome P450 2R1 is an enzyme that in humans is encoded by the CYP2R1 gene.[5][6][7]

CYP2R1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3C6G, 3CZH, 3DL9
Identifiers
Aliases	CYP2R1, cytochrome P450 family 2 subfamily R member 1
External IDs	OMIM: 608713 MGI: 2449771 HomoloGene: 75210 GeneCards: CYP2R1
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p15.2 Start 14,877,440 bp[1] End 14,892,252 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 F1 Start 114,549,682 bp[2] End 114,562,972 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • iron ion binding • metal ion binding • monooxygenase activity • heme binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen • oxidoreductase activity • vitamin D3 25-hydroxylase activity • steroid hydroxylase activity • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen Cellular component • organelle membrane • endoplasmic reticulum membrane • intracellular membrane-bounded organelle • membrane • endoplasmic reticulum • cytoplasm Biological process • response to ionizing radiation • vitamin D metabolic process • response to metal ion • vitamin metabolic process • calcitriol biosynthetic process from calciol • response to cesium ion • oxidation-reduction process • organic acid metabolic process • xenobiotic metabolic process • exogenous drug catabolic process • vitamin D biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	120227	244209
Ensembl	ENSG00000186104	ENSMUSG00000030670
UniProt	Q6VVX0	Q6VVW9
RefSeq (mRNA)	NM_024514 NM_001377214 NM_001377215 NM_001377216 NM_001377217 NM_001377227	NM_177382
RefSeq (protein)	NP_078790 NP_001364143 NP_001364144 NP_001364145 NP_001364146 NP_001364156	NP_796356
Location (UCSC)	Chr 11: 14.88 – 14.89 Mb	Chr 7: 114.55 – 114.56 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Vitamin D 25-hydroxylase is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. Found in the liver, this enzyme is a microsomal vitamin D hydroxylase that converts vitamin D into 25-hydroxyvitamin D (calcidiol), which is the major circulatory form of the vitamin.

Clinical significance

An inherited mutation in the CYP2R1 gene which results in the substitution of a proline for a leucine residue at codon 99 eliminates the enzyme activity and is associated with Vitamin D-dependent rickets type IB. Symptoms are low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency.[6] The gene product which it encodes, vitamin D 25-hydroxylase, has therefore been proposed as the key enzyme in the conversion of cholecalciferol (vitamin D₃) to calcidiol. Calcidiol is subsequently converted by the action of 25-hydroxyvitamin D3 1-alpha-hydroxylase to calcitriol, the active form of vitamin D₃ that binds to the vitamin D receptor (VDR) which mediates most of the physiological actions of the vitamin.[6]

Conversion of cholecalciferol to calcidiol as catalyzed by CYP2R1.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|{{{bSize}}}px|alt=Vitamin D Synthesis Pathway (view / edit)]]

Vitamin D Synthesis Pathway (view / edit)

1. The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Model organisms

Model organisms have been used in the study of CYP2R1 function. A conditional knockout mouse line called Cyp2r1^{tm1b(EUCOMM)Wtsi} was generated at the Wellcome Trust Sanger Institute.[8] Male and female animals underwent a standardized phenotypic screen[9] to determine the effects of deletion.[10][11][12][13] Additional screens performed: - In-depth immunological phenotyping[14]

Cyp2r1 knockout mouse phenotype

Characteristic	Phenotype
All data available at.[9][14]
Insulin	Normal
Homozygous viability at P14	Normal
Homozygous Fertility	Normal
Body weight	Normal
Neurological assessment	Normal
Grip strength	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology 16 Weeks	Normal
Peripheral blood leukocytes 16 Weeks	Normal
Heart weight	Normal
Salmonella infection	Normal
Spleen Immunophenotyping	Normal
Mesenteric Lymph Node Immunophenotyping	Normal
Epidermal Immune Composition	Normal
Influenza Challenge	Normal

References

1. GRCh38: Ensembl release 89: ENSG00000186104 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000030670 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Nelson DR (Dec 2002). "Comparison of P450s from human and fugu: 420 million years of vertebrate P450 evolution". Arch Biochem Biophys. 409 (1): 18–24. doi:10.1016/S0003-9861(02)00553-2. PMID 12464240.
6. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004-05-18). "Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase". Proc Natl Acad Sci U S A. 101 (20): 7711–7715. Bibcode:2004PNAS..101.7711C. doi:10.1073/pnas.0402490101. PMC 419671. PMID 15128933.
7. "Entrez Gene: CYP2R1 cytochrome P450, family 2, subfamily R, polypeptide 1".
8. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. S2CID 85911512.
9. "International Mouse Phenotyping Consortium".
10. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
11. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
12. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. S2CID 18872015.
13. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP (2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
14. "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

• Ramos-Lopez E, Brück P, Jansen T, et al. (2008). "CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans". Diabetes Metab. Res. Rev. 23 (8): 631–6. doi:10.1002/dmrr.719. PMID 17607662. S2CID 376070.
• Ramos-Lopez E, Brück P, Jansen T, et al. (2007). "CYP2R1-, CYP27B1- and CYP24-mRNA expression in German type 1 diabetes patients". J. Steroid Biochem. Mol. Biol. 103 (3–5): 807–10. doi:10.1016/j.jsbmb.2006.12.056. PMID 17223345. S2CID 23849431.
• Wjst M, Altmüller J, Faus-Kessler T, et al. (2006). "Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway". Respir. Res. 7: 60. doi:10.1186/1465-9921-7-60. PMC 1508148. PMID 16600026.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Shinkyo R, Sakaki T, Kamakura M, et al. (2004). "Metabolism of vitamin D by human microsomal CYP2R1". Biochem. Biophys. Res. Commun. 324 (1): 451–7. doi:10.1016/j.bbrc.2004.09.073. PMID 15465040.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.

External links

• Human CYP2R1 genome location and CYP2R1 gene details page in the UCSC Genome Browser.