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Information on EC 1.14.14.24 - vitamin D 25-hydroxylase and Organism(s) Homo sapiens and UniProt Accession Q6VVX0
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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 taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
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, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CYP2R1
-
-
-
-
vitamin D2 25-hydroxylase
-
-
-
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vitamin D3 25-hydroxylase
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-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-
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.
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-hydroxyvitamin D2 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D2 + NADP+ + H2O
-
-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
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
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-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
-
-
-
?
25-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyitamin D3 + NADP+ + H2O
-
additional product: 24,25-dihydroxyvitamin D3
-
?
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
-
-
?
additional information
?
-
no substrates: 25-hydroxyvitamin D3, cholesterol, 7-dehydrocholesterol
-
-
?
additional information
?
-
-
CYP2R1 shows no detectable 1alpha-hydroxylation activity
-
-
?
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
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
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
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
high levels of CYP2R1 expression compared to healthy adjacent tissue
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
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
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)
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
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
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
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
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
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
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
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
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Shinkyo, R.; Sakaki, T.; Kamakura, M.; Ohta, M.; Inouye, K.
Metabolism of vitamin D by human microsomal CYP2R1
Biochem. Biophys. Res. Commun.
324
451-457
2004
Homo sapiens
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
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)
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
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)
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)
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
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)
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
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
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
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