High impact information on CYP2R1

• These data identify CYP2R1 as a biologically relevant vitamin D 25-hydroxylase and reveal the molecular basis of a human genetic disease, selective 25-hydroxyvitamin D deficiency [1].
• This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15 [1].
• 2. The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity [1].
• Co-expression of CYP2R1 with vitamin D 1alpha-hydroxylase (CYP27B1) elicited additive activation of vitamin D3, whereas co-expression with vitamin D 24-hydroxylase (CYP24A1) caused inactivation [2].
• Thin layer chromatography and radioimmunoassays indicated that the secosteroid product of CYP2R1 was 25-hydroxyvitamin D3 [2].

Biological context of CYP2R1

• The deduced 544 amino acid sequence displays up to 39% identity to other CYP2 family members, with closest resemblance to CYP2R1 and is highly conserved between species [3].
• These results provide evidence against the existence of enzyme induction of vitamin D 25 hydroxylase by light [4].

Anatomical context of CYP2R1

• CYP2R1 mRNA is abundant in the liver and testis, and present at lower levels in other tissues [2].
• In addition, dermal fibroblasts contain mRNA of the vitamin D(3)-25-hydroxylases (CYP2R1 and CYP27A1) [5].
• CONCLUSION: CYP3A4 is a vitamin D 25-hydroxylase for vitamin D2 in human hepatic microsomes and hydroxylates both 1alpha(OH)D2 and 1alpha(OH)D3 [6].

Associations of CYP2R1 with chemical compounds

• CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase [7].
• RNA expression of vitamin D receptor (VDR) and of main enzymes involved in synthesis and metabolism of calcitriol (vitamin D-25-hydroxylase [25-OHase], 25-hydroxyvitamin D-1alpha-hydroxylase [1alpha-OHase], 1,25-dihydroxyvitamin D-24-hydroxylase [24-OHase]) was detected in BCCs and NS [8].

Other interactions of CYP2R1

• Thus, vitamin D metabolism by CYP2R1 was compared with human mitochondrial CYP27A1, which used to be considered a physiologically important vitamin D(3) 25-hydroxylase [9].
• In the CYP2 family, only CYP2R1 and CYP2U1 are conserved as recognizable subfamilies across species [10].
• Serum levels of 25(OH)D(3) and 1,25(OH)(2)D(3) were investigated in type 1 diabetes patients (n=173) and the mRNA expression of the CYP2R1, CYP27B1 and CYP24 genes in type 1 diabetes patients (n=33) and healthy controls (n=23) [11].
• CYP3A4, a vitamin D-25-hydroxylase, and CYP1A1 had the highest 24-hydroxylase activity with 1 alpha-hydroxyvitamin D(2) (1 alpha OHD(2)) as substrate [12].

References