CYP2R1

CYP2R1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCYP2R1, cytochrome P450 family 2 subfamily R member 1
External IDsOMIM: 608713; MGI: 2449771; HomoloGene: 75210; GeneCards: CYP2R1; OMA:CYP2R1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_177382

RefSeq (protein)

NP_796356

Location (UCSC)Chr 11: 14.88 – 14.89 MbChr 7: 114.15 – 114.16 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

CYP2R1 is cytochrome P450 2R1, an enzyme which is the principal vitamin D 25-hydroxylase.[5][6] In humans it is encoded by the CYP2R1 gene located on chromosome 11p15.2.[7] It is expressed in the endoplasmic reticulum in liver, where it performs the first step in the activation of vitamin D by catalyzing the formation of 25-hydroxyvitamin D.[8]

Vitamin D 25-hydroxylase activity is also possessed by some other cytochrome P450 enzymes, in particular CYP27A1, which is found in mitochondria.[8][9]

Function

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Conversion of cholecalciferol to calcidiol as catalyzed by CYP2R1.

CYP2R1 is a member of the cytochrome P450 superfamily of enzymes.[10] The cytochrome P450 proteins are mono-oxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids.[10]

CYP2R1 is present in the endoplasmic reticulum of the liver (the microsomal fraction). It has 25-hydroxylase activity, which converts cholecalciferol (vitamin D3) into calcifediol (25-hydroxyvitamin D3, also known as calcidiol), the major circulatory form of the vitamin.[8][9] CYP2R1 will also hydroxylate ergocalciferol (vitamin D2), derived from dietary sources, into 25-hydroxyvitamin D2 (ercalcidiol).[8] These 25-hydroxylated forms of vitamin D, together known as 25(OH)D, bind strongly to the vitamin D-binding protein in blood and are the principal circulating forms of vitamin D. These are commonly measured to determine a person's vitamin D status and establish vitamin D deficiency.[11]

Calcifediol is subsequently converted by the action of 25-hydroxyvitamin D3 1-alpha-hydroxylase to calcitriol, the active form of vitamin D3 which binds to the vitamin D receptor (VDR) and mediates most of the physiological hormonal actions of vitamin D.[5]

Clinical significance

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The conversion of vitamin D, especially cholecalciferol, to 25(OH)D (calcifediol) is one of the key steps in the vitamin D hormonal system. The CYP2R1 enzymatic activity achieving this process was previously thought to be constitutively expressed and stable, so that serum 25(OH)D was a measure of the supply of vitamin D.[9]

CYP2R1 is now known to be regulated, with variations in the expression and activity of CYP2R1 affecting circulating 25(OH)D.[9] Low levels of CYP2R1 activity have been found after 24 hour fasting, in obesity, type 1 and type 2 diabetes[12] and are decreased by glucocorticoids such as dexamethasone.[9] These conditions are known to be linked to low blood levels of 25(OH)D, where even large doses of vitamin D may not produce an improvement, which can be explained by enzyme activities being low.[9]

Polymorphic variations in CYP2R1

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Polymorphic variations in the CYP2R1 gene have the greatest effect on individual serum 25(OH)D concentrations compared with other gene variations.[13] An inherited mutation in the CYP2R1 gene L99P, 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. Another variant is K242N, where lysine at position 242 is substituted by asparagine, give a similar phenotype.[14] Symptoms are low circulating levels of 25(OH)D and classic symptoms of vitamin D deficiency.[5][15]

Interactive pathway map

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

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VitaminDSynthesis_WP1531Go to articleGo to articleGo to articleGo to articlego to articleGo to articleGo to articleGo to articlego to articlego to articlego to articlego to articleGo to articleGo to articlego to articleGo to articlego to articlego to articlego to articleGo to articlego to article
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VitaminDSynthesis_WP1531Go to articleGo to articleGo to articleGo to articlego to articleGo to articleGo to articleGo to articlego to articlego to articlego to articlego to articleGo to articleGo to articlego to articleGo to articlego to articlego to articlego to articleGo to articlego to article
|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".

Studies in mice

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Model organisms have been used in the study of CYP2R1 function. Mice have been generated with knockout of Cyp2r1 and both Cyp2r1 and Cyp27a1.[16] A conditional knockout mouse line called Cyp2r1tm1b(EUCOMM)Wtsi has been generated and animals have undergone a standardized phenotypic screen.[17][18]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000186104Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030670Ensembl, 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. ^ a b c Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW (September 2003). "De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase". J Biol Chem. 278 (39): 38084–93. doi:10.1074/jbc.M307028200. PMC 4450819. PMID 12867411.
  6. ^ Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (May 2004). "Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase". Proc Natl Acad Sci U S A. 101 (20): 7711–5. 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. ^ a b c d Bikle DD (March 2014). "Vitamin D metabolism, mechanism of action, and clinical applications". Chemistry & Biology. 21 (3): 319–29. doi:10.1016/j.chembiol.2013.12.016. PMC 3968073. PMID 24529992.
  9. ^ a b c d e f Bouillon R, Bikle D (November 2019). "Vitamin D Metabolism Revised: Fall of Dogmas". Journal of Bone and Mineral Research (Review). 34 (11): 1985–1992. doi:10.1002/jbmr.3884. PMC 9000993. PMID 31589774.
  10. ^ a b 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.
  11. ^ "Office of Dietary Supplements - Vitamin D". ods.od.nih.gov. 9 October 2020. Retrieved 7 March 2021.
  12. ^ 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.
  13. ^ Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, Medina-Gómez C, et al. (December 2018). "Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis". American Journal of Human Genetics. 103 (6): 1053. doi:10.1016/j.ajhg.2018.11.010. PMC 6288274. PMID 30526863.
  14. ^ Thacher TD, Levine MA (October 2017). "CYP2R1 mutations causing vitamin D-deficiency rickets". J Steroid Biochem Mol Biol. 173: 333–336. doi:10.1016/j.jsbmb.2016.07.014. PMID 27473561. S2CID 1693344.
  15. ^ Molin A, Wiedemann A, Demers N, Kaufmann M, Do Cao J, Mainard L, et al. (September 2017). "Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition?". Journal of Bone and Mineral Research. 32 (9): 1893–1899. doi:10.1002/jbmr.3181. PMID 28548312.
  16. ^ Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF (September 2013). "CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo". Proc Natl Acad Sci U S A. 110 (39): 15650–5. Bibcode:2013PNAS..11015650Z. doi:10.1073/pnas.1315006110. PMC 3785760. PMID 24019477.
  17. ^ "Cyp2r1 Mouse Gene Details". www.mousephenotype.org. International Mouse Phenotyping Consortium. Retrieved 8 March 2021.
  18. ^ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. (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.
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