Biology:CYP2R1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

CYP2R1 is cytochrome P450 2R1, an enzyme which is the principal vitamin D 25-hydroxylase.[1][2] In humans it is encoded by the CYP2R1 gene located on chromosome 11p15.2.[3] 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.[4]

Vitamin D 25-hydroxylase activity is also possessed by some other cytochrome P450 enzymes, in particular CYP27A1, which is found in mitochondria.[4][5]

Function

Conversion of cholecalciferol to calcidiol as catalyzed by CYP2R1.

CYP2R1 is a member of the cytochrome P450 superfamily of enzymes.[6] The cytochrome P450 proteins are mono-oxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids.[6]

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.[4][5] CYP2R1 will also hydroxylate ergocalciferol (vitamin D2), derived from dietary sources, into 25-hydroxyvitamin D2 (ercalcidiol).[4] 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.[7]

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.[1]

Clinical significance

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.[5]

CYP2R1 is now known to be regulated, with variations in the expression and activity of CYP2R1 affecting circulating 25(OH)D.[5] Low levels of CYP2R1 activity have been found after 24 hour fasting, in obesity, type 1 and type 2 diabetes[8] and are decreased by glucocorticoids such as dexamethasone.[5] 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.[5]

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.[9] 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.[10] Symptoms are low circulating levels of 25(OH)D and classic symptoms of vitamin D deficiency.[1][11]

Interactive pathway map

Studies in mice

Model organisms have been used in the study of CYP2R1 function. Mice have been generated with knockout of Cyp2r1 and both Cyp2r1 and Cyp27a1.[12] A conditional knockout mouse line called Cyp2r1tm1b(EUCOMM)Wtsi has been generated and animals have undergone a standardized phenotypic screen.[13][14]

References

  1. ↑ 1.0 1.1 1.2 "De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase". J Biol Chem 278 (39): 38084–93. September 2003. doi:10.1074/jbc.M307028200. PMID 12867411. 
  2. ↑ "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. May 2004. doi:10.1073/pnas.0402490101. PMID 15128933. Bibcode: 2004PNAS..101.7711C. 
  3. ↑ "Entrez Gene: CYP2R1 cytochrome P450, family 2, subfamily R, polypeptide 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=120227. 
  4. ↑ 4.0 4.1 4.2 4.3 "Vitamin D metabolism, mechanism of action, and clinical applications". Chemistry & Biology 21 (3): 319–29. March 2014. doi:10.1016/j.chembiol.2013.12.016. PMID 24529992. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Vitamin D Metabolism Revised: Fall of Dogmas". Journal of Bone and Mineral Research 34 (11): 1985–1992. November 2019. doi:10.1002/jbmr.3884. PMID 31589774. 
  6. ↑ 6.0 6.1 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. 
  7. ↑ "Office of Dietary Supplements - Vitamin D" (in en). 9 October 2020. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/. 
  8. ↑ "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. 2008. doi:10.1002/dmrr.719. PMID 17607662. 
  9. ↑ "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. December 2018. doi:10.1016/j.ajhg.2018.11.010. PMID 30526863. 
  10. ↑ "CYP2R1 mutations causing vitamin D-deficiency rickets". J Steroid Biochem Mol Biol 173: 333–336. October 2017. doi:10.1016/j.jsbmb.2016.07.014. PMID 27473561. 
  11. ↑ "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. September 2017. doi:10.1002/jbmr.3181. PMID 28548312. 
  12. ↑ "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. September 2013. doi:10.1073/pnas.1315006110. PMID 24019477. Bibcode: 2013PNAS..11015650Z. 
  13. ↑ "Cyp2r1 Mouse Gene Details". International Mouse Phenotyping Consortium. https://www.mousephenotype.org/data/genes/MGI:2449771. 
  14. ↑ "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. Jun 2011. doi:10.1038/nature10163. PMID 21677750. 

External links



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