CYP2R1 is cytochrome P450 2R1, an enzyme which is the principal vitamin D 25-hydroxylase.[5][6] In humans it is encoded by the CYP2R1gene 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
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]
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
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
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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]
^ abNelson 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. PMID12464240.
^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. PMID17607662. S2CID376070.