CYP2R1

File:Reaction - cholecalciferol to calcidiol (vertical).png

CYP2R1 is a member of the cytochrome P450 superfamily of enzymes.{{cite journal | author = Nelson DR | title = Comparison of P450s from human and fugu: 420 million years of vertebrate P450 evolution | journal = Arch Biochem Biophys | volume = 409 | issue = 1 | pages = 18–24 |date=Dec 2002 | pmid = 12464240 | doi =10.1016/S0003-9861(02)00553-2 }} The cytochrome P450 proteins are mono-oxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids.

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. CYP2R1 will also hydroxylate ergocalciferol (vitamin D₂), derived from dietary sources, into 25-hydroxyvitamin D₂ (ercalcidiol). 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.{{cite web |title=Office of Dietary Supplements - Vitamin D |url=https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ |website=ods.od.nih.gov |date=9 October 2020 |access-date=7 March 2021 |language=en}}

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.

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.

CYP2R1 is now known to be regulated, with variations in the expression and activity of CYP2R1 affecting circulating 25(OH)D. Low levels of CYP2R1 activity have been found after 24 hour fasting, in obesity, type 1 and type 2 diabetes{{cite journal | vauthors=Ramos-Lopez E, Brück P, Jansen T |title=CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. |journal=Diabetes Metab. Res. Rev. |volume=23 |issue= 8 |pages= 631–6 |year= 2008 |pmid= 17607662 |doi= 10.1002/dmrr.719 |s2cid=376070 |display-authors=etal}} and are decreased by glucocorticoids such as dexamethasone. 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.

Polymorphic variations in the CYP2R1 gene have the greatest effect on individual serum 25(OH)D concentrations compared with other gene variations.{{cite journal | vauthors = Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, Medina-Gómez C, et al. | title = Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis | journal = American Journal of Human Genetics | volume = 103 | issue = 6 | pages = 1053 | date = December 2018 | pmid = 30526863 | pmc = 6288274 | doi = 10.1016/j.ajhg.2018.11.010 | url = }} 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.{{cite journal | vauthors = Thacher TD, Levine MA | title = CYP2R1 mutations causing vitamin D-deficiency rickets | journal = J Steroid Biochem Mol Biol | volume = 173 | issue = | pages = 333–336 | date = October 2017 | pmid = 27473561 | doi = 10.1016/j.jsbmb.2016.07.014 | s2cid = 1693344 | url = }} Symptoms are low circulating levels of 25(OH)D and classic symptoms of vitamin D deficiency.{{cite journal | vauthors = Molin A, Wiedemann A, Demers N, Kaufmann M, Do Cao J, Mainard L, et al.| title = Vitamin D-Dependent Rickets Type 1B (25-Hydroxylase Deficiency): A Rare Condition or a Misdiagnosed Condition? | journal = Journal of Bone and Mineral Research | volume = 32 | issue = 9 | pages = 1893–1899 | date = September 2017 | pmid = 28548312 | doi = 10.1002/jbmr.3181 | url = | doi-access = free }}

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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.{{cite journal | vauthors = Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF | title = CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo | journal = Proc Natl Acad Sci U S A | volume = 110 | issue = 39 | pages = 15650–5 | date = September 2013 | pmid = 24019477 | pmc = 3785760 | doi = 10.1073/pnas.1315006110 | bibcode = 2013PNAS..11015650Z | url = | doi-access = free }} A conditional knockout mouse line called Cyp2r1^{tm1b(EUCOMM)Wtsi} has been generated and animals have undergone a standardized phenotypic screen.{{cite web |title=Cyp2r1 Mouse Gene Details |url=https://www.mousephenotype.org/data/genes/MGI:2449771 |website=www.mousephenotype.org |publisher=International Mouse Phenotyping Consortium |access-date=8 March 2021}}{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al.| title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}

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• {{UCSC gene info|CYP2R1}}

{{PDB Gallery|geneid=120227}}

{{Cytochrome P450}}

{{Dioxygenases}}

{{Enzymes}}

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Category:EC 1.14.13

Category:Cytochrome P450