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Information on EC 1.14.14.24 - vitamin D 25-hydroxylase
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1.14.14.24 vitamin D 25-hydroxylaseIUBMB Comments
A microsomal enzyme isolated from human and mouse liver that bioactivates vitamin D3. While multiple isoforms (CYP27A1, CYP2J2/3, CYP3A4, CYP2D25 and CYP2C11) are able to catalyse the reaction in vitro, only CYP2R1 is thought to catalyse the reaction in humans in vivo . The direct electron donor to the enzyme is EC 1.6.2.4, NADPH---hemoprotein reductase.
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Word Map
- 1.14.14.24
-
25-hydroxyvitamin
- cyp27b1
- cyp2j2
-
arachidonic
-
25-hydroxylation
-
epoxyeicosatrienoic
- epoxygenase
- rickets
-
d-related
-
male-specific
- 7-dehydrocholesterol
- cholecalciferol
- astemizole
- ebastine
- terfenadine
-
d-associated
- medicine
-
1alpha-hydroxylation
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
cyp2r1, cyp2j3, vitamin d 25-hydroxylase, cytochrome p450 2c11, cytochrome p450 2j2, cyp2d25, vitamin d-25-hydroxylase, cytochrome p450 2r1, cytochrome p450 2j3, vitamin d2 25-hydroxylase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CYP2R1
-
-
-
-
CYP2R1
cytochrome P450 2R1
EC 1.14.13.159
-
-
formerly
-
VDH
vitamin D 25-hydroxylase
vitamin D2 25-hydroxylase
-
-
-
-
vitamin D3 25-hydroxylase
-
-
-
-
vitamin D3 hydroxylase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
calciol + O2 + [reduced NADPH-hemoprotein reductase] = calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
calciol,NADPH-hemoprotein reductase:oxygen oxidoreductase (25-hydroxylating)
A microsomal enzyme isolated from human and mouse liver that bioactivates vitamin D3. While multiple isoforms (CYP27A1, CYP2J2/3, CYP3A4, CYP2D25 and CYP2C11) are able to catalyse the reaction in vitro, only CYP2R1 is thought to catalyse the reaction in humans in vivo [4]. The direct electron donor to the enzyme is EC 1.6.2.4, NADPH---hemoprotein reductase.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
1alpha,25-dihydroxyvitamin D2 + O2 + [reduced NADPH-hemoprotein reductase] + H+
1alpha,25,26-trihydroxyvitamin D2 + [oxidized NADPHhemoprotein reductase] + H2O
-
-
-
?
1alpha,25-dihydroxyvitamin D3 + O2 + [reduced NADPH-hemoprotein reductase] + H+
1alpha,25,26-trihydroxyvitamin D3 + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
1alpha-hydroxy-vitamin D2 + O2 + [reduced NADPH-hemoprotein reductase] + H+
1alpha,25-dihydroxy-vitamin D2 + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
1alpha-hydroxy-vitamin D3 + O2 + [reduced NADPH-hemoprotein reductase] + H+
1alpha,25-dihydroxy-vitamin D3 + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
-
?
1alpha-hydroxycholecalciferol + O2 + NADPH + H+
1alpha,25-dihydroxycholecalciferol + NADP+ + H2O
-
-
-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxy-vitamin D3 + NADP+ + H2O
-
-
-
-
?
25-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyitamin D3 + NADP+ + H2O
-
additional product: 24,25-dihydroxyvitamin D3
-
?
calciferol + O2 + [reduced NADPH-hemoprotein reductase]
25-hydroxy-vitamin D2 + [oxidized NADPH-hemoprotein reductase] + H2O
enzyme CYP2R1 hydroxylates vitamin D2 at position C-25 position
-
-
?
calciferol + O2 + [reduced NADPH-hemoprotein reductase]
25-hydroxyergocalciferol + [oxidized NADPH-hemoprotein reductase] + H2O
enzyme CYP2R1 hydroxylates vitamin D2 at position C-25 position
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
cholecalciferol + O2 + NADPH + H+
25-hydroxycholecalciferol + NADP+ + H2O
-
at about 20% of the rate with 1alpha-hydroxycholecalciferol
-
-
?
ebastin + O2 + NADPH + H+
? + NADP+ + H2O
histamine H1-recepter antagonist
-
-
?
1alpha-hydroxyvitamin D2 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D2 + NADP+ + H2O
-
-
-
?
1alpha-hydroxyvitamin D2 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D2 + NADP+ + H2O
-
-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
-
-
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
enzyme CYP2R1 hydroxylates vitamin D3 at position C-25 position
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
-
enzyme CYP2R1 hydroxylates vitamin D3 at position C-25 position
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
the microsomal enzyme CYP2R1 catalyzes C-25 hydroxylation of vitamin D3 to an active vitamin D receptor ligand in the liver and other organs
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
calciol i.e. cholecalciferol i.e. vitamin D3. Calcidiol i.e. 25-hydroxyvitamin D3
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
vitamin D2 + O2 + NADPH + H+
25-hydroxyvitamin D2 + NADP+ + H2O
-
-
-
?
vitamin D2 + O2 + NADPH + H+
25-hydroxyvitamin D2 + NADP+ + H2O
-
-
-
?
vitamin D3 + O2 + NADPH + H+
1alpha, 25-dihydroxy-vitamin D3 + NADP+ + H2O
-
major products are 25-hydroxy-vitamin D3 and 1alpha, 25-dihydroxy-vitamin D3, plus minor amounts of 26-hydroxy-vitamin D3
-
?
vitamin D3 + O2 + NADPH + H+
1alpha, 25-dihydroxy-vitamin D3 + NADP+ + H2O
-
major products are 25-hydroxy-vitamin D3 and 1alpha, 25-dihydroxy-vitamin D3, plus minor amounts of 26-hydroxy-vitamin D3
-
?
vitamin D3 + O2 + NADPH + H+
25-hydroxy-vitamin D3 + NADP+ + H2O
-
major products are 25-hydroxy-vitamin D3 and 1alpha, 25-dihydroxy-vitamin D3, plus minor amounts of 26-hydroxy-vitamin D3. Data indicate that Vdh first hydroxylates the C-25 position of vitamion D3 and subsequently hydroxylates the C1alpha position of 25-hydroxy-vitamin D3
-
?
vitamin D3 + O2 + NADPH + H+
25-hydroxy-vitamin D3 + NADP+ + H2O
-
major products are 25-hydroxy-vitamin D3 and 1alpha, 25-dihydroxy-vitamin D3, plus minor amounts of 26-hydroxy-vitamin D3. Data indicate that Vdh first hydroxylates the C-25 position of vitamion D3 and subsequently hydroxylates the C1alpha position of 25-hydroxy-vitamin D3
-
?
vitamin D3 + O2 + NADPH + H+
25-hydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
vitamin D3 + O2 + NADPH + H+
25-hydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
vitamin D3 + O2 + NADPH + H+
25-hydroxyvitamin D3 + NADP+ + H2O
-
-
plus some 26-hydroxyvitamin D3
-
?
additional information
?
-
-
CYP2R1 shows no detectable 1alpha-hydroxylation activity
-
-
?
additional information
?
-
no substrates: 25-hydroxyvitamin D3, cholesterol, 7-dehydrocholesterol
-
-
?
additional information
?
-
-
no substrates: benzphetamine, 7-ethoxycoumarin, and benzo[a]pyrene
-
-
?
additional information
?
-
the descending order of 25-hydroxylation by CYP2C11 is 1-hydroxyvitamin D3, 1-hydroxyvitamin D2, vitamin D, vitamin D3. 24-Hydroxylation of 1alpha-hydroxyvitamin D3 is very low and does not occur with 1-alpha-hydroxyvitamin D2
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
calciferol + O2 + [reduced NADPH-hemoprotein reductase]
25-hydroxy-vitamin D2 + [oxidized NADPH-hemoprotein reductase] + H2O
enzyme CYP2R1 hydroxylates vitamin D2 at position C-25 position
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
enzyme CYP2R1 hydroxylates vitamin D3 at position C-25 position
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
-
enzyme CYP2R1 hydroxylates vitamin D3 at position C-25 position
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
the microsomal enzyme CYP2R1 catalyzes C-25 hydroxylation of vitamin D3 to an active vitamin D receptor ligand in the liver and other organs
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
-
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
activity is completely lost when the electron-transferring system is replaced by that of microsomes, i.e. NADPH-cytochrome P-450 reductase purified from rat liver microsomes. The omission of cytochrome P-450, adrenodoxin, or NADPH-adrenodoxin reductase results in complete loss of enzyme activity
-
heme
-
addition of NAD+ in presence of 1alpha-hydroxy-vitamin D2 to CYP2R1 induces a typical type I spectrum, indicating a change of the heme iron of CYP2R1 from a low-spin state to a high-spin state
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Iron
-
addition of NAD+ in presence of 1alpha-hydroxy-vitamin D2 to CYP2R1 induces a typical type I spectrum, indicating a change of the heme iron of CYP2R1 from a low-spin state to a high-spin state
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
not inhibitory: aminoglutethimide. The enzyme activity was markedly inhibited in an atmosphere of CO:Os:Nz, 40:20:40
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
partially methylated beta-cyclodextrin
activity increases approximately 10fold when partially methylated beta-cyclodextrin is present in the reaction at a final concentration of 0.05%
-
additional information
-
stimulation by addition of cytosolic protein, which remains after boiling the cytosolic protein
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0071
25-hydroxy-vitamin D3
30°C, pH not specified in the publication
0.0135
vitamin D3
30°C, pH not specified in the publication
0.02
vitamin D3
-
mitochondrial enzyme, pH not specified in the publication, temperature not specified in the publication
0.032
vitamin D3
mutant T70R/V156L/E216M/E384R, 30°C, pH not specified in the publication
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
male-specific hepatic microsomal vitamin D 25-hydroxlase CYP2C11
UniProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
high levels of CYP2R1 expression compared to healthy adjacent tissue
brenda
additional information
additional information
quantitative real-time PCR enzyme expression analysis, no or low expression in kidney and ovaries
brenda
additional information
-
quantitative real-time PCR enzyme expression analysis, no or low expression in kidney and ovaries
-
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
heavy mitochondrial fraction, highest activity found
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
malfunction
compared with noncarriers, carriers of 4 risk alleles of rs10741657 have lowest concentrations and smallest increases in 25-hydroxy-vitamin D concentrations after 4 UVB treatments and largest decreases in 25-hydroxy-vitamin D concentrations after 6-months of consumption of vitamin D3fortified bread and milk. Common genetic variants rs10741657 and rs10766197 in vitamin D25-hydroxylase (CYP2R1) predict 25-hydroxy-vitamin D concentrations
malfunction
enzyme-deficient Cyp2r1-/- mice show greater than 50% reduction in serum 25-hydroxyvitamin D3 level, while the 1alpha,25-dihydroxyvitamin D3 level in the serum remains unchanged. A double knockout of Cyp2r1 and Cyp27a1, the enzyme responsible for the 1alpha-hydroxylation step, maintain a similar circulating level of 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3
malfunction
-
enzyme-deficient Cyp2r1-/- mice show greater than 50% reduction in serum 25-hydroxyvitamin D3 level, while the 1alpha,25-dihydroxyvitamin D3 level in the serum remains unchanged. A double knockout of Cyp2r1 and Cyp27a1, the enzyme responsible for the 1alpha-hydroxylation step, maintain a similar circulating level of 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3
-
metabolism
the cross talk from the bone to the testis of the vitamin D 25-hydroxylase CYP2R1 involves osteocalcin, which is produced by the osteoblasts and stimulates the production of testosterone by the Leydig cells through its putative receptor GPRC6A, a cation-sensing G-protein-coupled receptor. Action of osteocalcin on CYP2R1 expression and 25-hydroxyvitamin D production in a mouse Leydig cell line MA-10
metabolism
the microsomal enzyme CYP2R1 catalyzes C-25 hydroxylation of vitamin D3 to an active vitamin D receptor ligand in the liver and other organs
physiological function
expression of CYP2R1 in HEK 293 cells leads to the transcriptional activation of the vitamin D receptor when either vitamin D2 or D3 is added to the medium. Co-expression of CYP2R1 with vitamin D 1-hydroxylase CYP27B1 elicits additive activation of vitamin D3, whereas co-expression with vitamin D 24-hydroxylase CYP24A1 causes inactivation
physiological function
in male rats, hypophysectomy reduces body weight by 40% and liver weight by 50%. 25-Hydroxylase activity is reduced by 64%, 24-hydroxylase activity is reduced by 52%, and hepatic microsomal CYP2C11 mRNA is decreased by 73% compared with the values of sham-operated animals
physiological function
-
the absence of either of the two key hydroxylases, i.e., 25-hydroxylase and 1alpha-hydroxylase, neither inhibits nor enhances the development of experimental autoimmune encephalomyelitis in a mice model
physiological function
CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. A second enzyme is another contributor to this important step in vitamin D activation
physiological function
CYP2R1 is a physiologically important vitamin D 25-hydroxylase. Vitamin D3 is initially converted to 25(OH)D3 in the liver, and then 25(OH)D 3 is converted to a functionally active form, namely 1alpha,25(OH)2D3, in the kidney. 1alpha,25(OH)2D3 plays essential roles in calcium and phosphate homeostasis, cell differentiation and immunology. Metabolic activation of vitamin D3 is performed by the hepatic vitamin D3 25-hydroxylase microsomal CYP2R1, and mitochondrial 1alpha-hydroxylase CYP27A1
physiological function
the microsomal vitamin D 25-hydroxylase plays an important role in converting dietary vitamin D to active metabolite, 25-(OH)D3. 1,25(OH)2D3 regulates CYP2R1 gene expression in oral squamous cell carcinoma tumor cells
physiological function
-
CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. A second enzyme is another contributor to this important step in vitamin D activation
-
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CP2R1_HUMAN
501
1
57359
Swiss-Prot
Secretory Pathway (Reliability: 2)
CP2R1_MOUSE
501
1
57313
Swiss-Prot
Secretory Pathway (Reliability: 1)
CP2DP_PIG
500
2
56512
Swiss-Prot
Secretory Pathway (Reliability: 1)
CP2CB_RAT
500
0
57181
Swiss-Prot
other Location (Reliability: 3)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
52500
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
homology modeling. The relative position of Val391 in the beta3a-strand of a homology model and the crystal structure of rat CYP24A1 are consistent with hydrophobic contact of Val391 and the substrate side chain near C21
in complex with vitamin D3, to 1.0 A resolution. The CYP2R1 structure adopts a closed conformation with the substrate access channel being covered by the ordered B'-helix and slightly opened to the surface, which defines the substrate entrance point. The active site is lined by conserved, mostly hydrophobic residues. Vitamin D3 is bound in an elongated conformation with the aliphatic side-chain pointing toward the heme. The structure reveals the secosteroid binding mode in an extended active site
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
L99P
-
mutation identified in a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual is homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2, leading to the substitution of a proline for an evolutionarily conserved leucine and eliminating vitamin D 25-hydroxylase enzyme activity
V391L
mutation converts the enzyme from a catabolic 1alpha,25-dihydroxyvitamin D3-24-hydroxylase into an anabolic 1alpha-hydroxy-vitamin-D3-25-hydroxylase, which forms the hormone, 1alpha,25-dihydroxyvitamin D3. Mutant enzyme retains its basal ability to catabolize 1alpha,25-dihydroxyvitamin D3 via C24 hydroxylation, and can also produce calcitroic acid
V391L/A326G
mutant enzyme continues to form 1alpha,25-dihydroxyvitamin D3 from 1alpha-hydroxyvitamin D3, but this initial product is diverted via the C23 hydroxylation pathway into the 26,23-lactone. About 40-60% of wild-type activity
T70R/V156L/E216M/E384R
21fold increase in hydroxylase activity
T70R/V156S/E216A/E384R
7.9fold increase in hydroxylase activity
T70R/V156L/E216M/E384R
-
21fold increase in hydroxylase activity
-
A241G/L243V/F244L/P245R/R246F
-
mutation in substrate recognition site 3, to the equivalent residues in CYP2D6, an enzyme not active in 25-hydroxylation. The 25-hydroxylase activity of the mutant is completely lost whereas the activity toward tolterodine remains virtually unaffected
additional information
additional information
construction of null mutant enzyme-deficient Cyp2r1-/- mice, that show greater than 50% reduction in serum 25-hydroxyvitamin D3 level, while the 1alpha,25-dihydroxyvitamin D3 level in the serum remains unchanged. A double knockout of Cyp2r1 and Cyp27a1, the enzyme responsible for the 1alpha-hydroxylation step, maintain a similar circulating level of 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3
additional information
-
construction of null mutant enzyme-deficient Cyp2r1-/- mice, that show greater than 50% reduction in serum 25-hydroxyvitamin D3 level, while the 1alpha,25-dihydroxyvitamin D3 level in the serum remains unchanged. A double knockout of Cyp2r1 and Cyp27a1, the enzyme responsible for the 1alpha-hydroxylation step, maintain a similar circulating level of 25-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3
-
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli
functional recombinant expression of human CYP2R1 in Saccharomyces cerevisiae
gene CYP2R1, real-time RT-PCR enzyme expression analysis, transient expression of hCYP2R1 promoter (-2 kb)-luciferase reporter plasmid, stimulation with 1,25(OH)2D3 causes a 4.3fold increase in promoter activity. In addition, 1,25-(OH)2D3 significantly increased c-Fos, p-c-Jun expression, and c-Jun N-terminal kinase activity in these cells. AP-1 is a downstream effector of 1,25(OH)2D3 signaling to modulate CYP2R1 gene expression in OSCC tumor cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
1alpha,25-dihydroxyvitamin D3 increases CYP2R1 gene and and vitamin D receptor mRNA expression in human oral squamous cell carcinoma tumor cells. JNK inhibitor suppresses 1,25 (OH)2D3 stimulation of hCYP2R1 gene promoter activity compared to unstimulated cells
CYP2J3 mRNA is is expressed at a level similar to that of CYP27A1 without marked sexual dimorphism
genes CYP2R1 encoding vitamin D 25-hydroxylase, CYP27B1 encoding 25-hydroxyvitamin D-1 alpha hydroxylase and CYP24A1 encoding 1,25-dihydroxyvitamin D(3) 24-hydroxylase are upregulated in clear cell renal cell carcinomas compared with normal tissue. CYP24A1 displays a significantly higher expression in tumours than CYP27B1 and CYP2R1, whereas no differences in the expression of these genes are found in healthy renal tissue
in male rats, hepatic microsomal CYP2C11 mRNA is decreased by 73% upon hypophysectomy
the luteinizing hormone induces the enzyme. MA-10 cell stimulation with either human chorionic gonadotropin or uncarboxylated-osteocalcin increases CYP2R1 protein expression in a dose-dependent manner and, in turn, increases the release of 25-hydroxy-vitamin D in culture medium. Osteocalcin, in particular uncarboxylated osteocalcin, stimulates 25-hydroxylation of vitamin D in Leydig cells through a direct effect on the expression of the main actor in the 25-hydroxylase activity of vitamin D, the CYP2R1 protein
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
experimental autoimmune encephalomyelitis development is markedly suppressed in mice lacking the vitamin D receptor and partially suppressed in vitamin D-insufficient mice. The absence of either of the two key hydroxylases, i.e., 25-hydroxylase and 1alpha-hydroxylase, neither inhibits nor enhances the development of experimental autoimmune encephalomyelitis
medicine
-
mutation L99P has been identified in a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual is homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2, leading to the substitution of a proline for an evolutionarily conserved leucine and eliminating vitamin D 25-hydroxylase enzyme activity
medicine
genes CYP2R1 encoding vitamin D 25-hydroxylase, CYP27B1 encoding 25-hydroxyvitamin D-1 alpha hydroxylase and CYP24A1 encoding 1,25-dihydroxyvitamin D(3) 24-hydroxylase are upregulated in clear cell renal cell carcinomas compared with normal tissue. CYP24A1 displays a significantly higher expression in tumours than CYP27B1 and CYP2R1, whereas no differences in the expression of these genes are found in healthy renal tissue. Gene expression of CYP2R1, CYP27B1 and CYP24A does not differ between pathological classifications
medicine
testis samples from patients with hypospermatogenesis and Sertoli-cell-only syndrome show a lower gene and protein expression of isoform CYP2R1 and a colocalization with INSL-3, a Leydig cell marker. In all testiculopathic patients 25-hydroxyvitamin D levels are significantly lower and parathyroid hormone levels higher compared to controls. Testiculopathic patients show osteopenia and osteoporosis despite normal testosterone levels compared with controls both with increased bone-marker levels and altered dual-energy X-ray absorptiometry in the femoral neck and lumbar spine
medicine
vitamin D analogus can be potential therapeutic agents to control oral squamous cell carcinoma tumor cell tumor progression
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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Rattus norvegicus (P08683)
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brenda
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brenda
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263
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1988
Rattus norvegicus
brenda
Cheng, J.B.; Motola, D.L.; Mangelsdorf, D.J.; Russell, D.W.
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278
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2003
Mus musculus (Q6VVW9)
brenda
Yamasaki, T.; Izumi, S.; Ide, H.; Ohyama, Y.
Identification of a novel rat microsomal vitamin D3 25-hydroxylase
J. Biol. Chem.
279
22848-22856
2004
Rattus norvegicus (P51590)
brenda
Kaufmann, M.; Prosser, D.E.; Jones, G.
Bioengineering anabolic vitamin D-25-hydroxylase activity into the human vitamin D catabolic enzyme, cytochrome P450 CYP24A1, by a V391L mutation
J. Biol. Chem.
286
28729-28737
2011
Homo sapiens (Q07973), Homo sapiens
brenda
Strushkevich, N.; Usanov, S.A.; Plotnikov, A.N.; Jones, G.; Park, H.W.
Structural analysis of CYP2R1 in complex with vitamin D3
J. Mol. Biol.
380
95-106
2008
Homo sapiens (Q6VVX0)
brenda
Cheng, J.B.; Levine, M.A.; Bell, N.H.; Mangelsdorf, D.J.; Russell, D.W.
Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
Proc. Natl. Acad. Sci. USA
101
7711-7715
2004
Homo sapiens
brenda
Wang, Y.; Marling, S.J.; Zhu, J.G.; Severson, K.S.; DeLuca, H.F.
Development of experimental autoimmune encephalomyelitis (EAE) in mice requires vitamin D and the vitamin D receptor
Proc. Natl. Acad. Sci. USA
109
8501-8504
2012
Mus musculus
brenda
Aiba, I.; Yamasaki, T.; Shinki, T.; Izumi, S.; Yamamoto, K.; Yamada, S.; Terato, H.; Ide, H.; Ohyama, Y.
Characterization of rat and human CYP2J enzymes as Vitamin D 25-hydroxylases
Steroids
71
849-856
2006
Homo sapiens (P51589), Homo sapiens, Rattus norvegicus (P51590)
brenda
Urbschat, A.; Paulus, P.; von Quernheim, Q.F.; Brueck, P.; Badenhoop, K.; Zeuzem, S.; Ramos-Lopez, E.
Vitamin D hydroxylases CYP2R1, CYP27B1 and CYP24A1 in renal cell carcinoma
Eur. J. Clin. Invest.
43
1282-1290
2013
Homo sapiens (Q6VVX0)
brenda
Foresta, C.; Strapazzon, G.; De Toni, L.; Perilli, L.; Di Mambro, A.; Muciaccia, B.; Sartori, L.; Selice, R.
Bone mineral density and testicular failure: evidence for a role of vitamin D 25-hydroxylase in human testis
J. Clin. Endocrinol. Metab.
96
E646-E652
2011
Homo sapiens (Q6VVX0), Homo sapiens
brenda
Nissen, J.; Vogel, U.; Ravn-Haren, G.; Andersen, E.W.; Madsen, K.H.; Nex?, B.A.; Andersen, R.; Mejborn, H.; Bjerrum, P.J.; Rasmussen, L.B.; Wulf, H.C.
Common variants in CYP2R1 and GC genes are both determinants of serum 25-hydroxyvitamin D concentrations after UVB irradiation and after consumption of vitamin D3-fortified bread and milk during winter in Denmark
Am. J. Clin. Nutr.
101
218-227
2015
Homo sapiens (Q6VVX0)
brenda
Yasuda, K.; Endo, M.; Ikushiro, S.; Kamakura, M.; Ohta, M.; Sakaki, T.
UV-dependent production of 25-hydroxyvitamin D2 in the recombinant yeast cells expressing human CYP2R1
Biochem. Biophys. Res. Commun.
434
311-315
2013
Homo sapiens (Q6VVX0), Homo sapiens
brenda
De Toni, L.; De Filippis, V.; Tescari, S.; Ferigo, M.; Ferlin, A.; Scattolini, V.; Avogaro, A.; Vettor, R.; Foresta, C.
Uncarboxylated osteocalcin stimulates 25-hydroxy vitamin D production in Leydig cell line through a GPRC6a-dependent pathway
Endocrinology
155
4266-4274
2014
Mus musculus (Q6VVW9), Mus musculus
brenda
Sundaram, K.; Sambandam, Y.; Tsuruga, E.; Wagner, C.L.; Reddy, S.V.
1alpha,25-dihydroxyvitamin D3 modulates CYP2R1 gene expression in human oral squamous cell carcinoma tumor cells
Horm. Cancer
5
90-97
2014
Homo sapiens (Q6VVX0), Homo sapiens
brenda
Zhu, J.G.; Ochalek, J.T.; Kaufmann, M.; Jones, G.; Deluca, H.F.
CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo
Proc. Natl. Acad. Sci. USA
110
15650-15655
2013
Mus musculus (Q6VVW9), Mus musculus C57BL/6 (Q6VVW9)
brenda
Ahn, J.; Yu, K.; Stolzenberg-Solomon, R.; Simon, K.C.; McCullough, M.L.; Gallicchio, L.; Jacobs, E.J.; Ascherio, A.; Helzlsouer, K.; Jacobs, K.B.; Li, Q.; Weinstein, S.J.; Purdue, M.; Virtamo, J.; Horst, R.; Wheeler, W.; Chanock, S.; Hunter, D.J.; Hayes, R.B.; Kraft, P.; Albanes, D.
Genome-wide association study of circulating vitamin D levels
Hum. Mol. Genet.
19
2739-2745
2010
Homo sapiens (Q6VVX0), Homo sapiens
brenda
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