Information on EC 1.14.14.24 - vitamin D 25-hydroxylase and Organism(s) Homo sapiens

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
1.14.14.24
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RECOMMENDED NAME
GeneOntology No.
vitamin D 25-hydroxylase
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
vitamin D3 biosynthesis
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vitamin D3 metabolism
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Steroid biosynthesis
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Metabolic pathways
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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.
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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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 D3–fortified bread and milk. Common genetic variants rs10741657 and rs10766197 in vitamin D25-hydroxylase (CYP2R1) predict 25-hydroxy-vitamin D concentrations
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
1alpha-hydroxy-vitamin D2 + O2 + [reduced NADPH-hemoprotein reductase] + H+
1alpha,25-dihydroxy-vitamin D2 + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
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-
-
-
?
1alpha-hydroxy-vitamin D3 + O2 + [reduced NADPH-hemoprotein reductase] + H+
1alpha,25-dihydroxy-vitamin D3 + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
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-
-
-
?
1alpha-hydroxyvitamin D2 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D2 + NADP+ + H2O
show the reaction diagram
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-
-
?
1alpha-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyvitamin D3 + NADP+ + H2O
show the reaction diagram
25-hydroxyvitamin D3 + O2 + NADPH + H+
1alpha,25-dihydroxyitamin D3 + NADP+ + H2O
show the reaction diagram
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additional product: 24,25-dihydroxyvitamin D3
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?
calciferol + O2 + [reduced NADPH-hemoprotein reductase]
25-hydroxy-vitamin D2 + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
enzyme CYP2R1 hydroxylates vitamin D2 at position C-25 position
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?
calciferol + O2 + [reduced NADPH-hemoprotein reductase]
25-hydroxyergocalciferol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
enzyme CYP2R1 hydroxylates vitamin D2 at position C-25 position
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?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
vitamin D2 + O2 + NADPH + H+
25-hydroxy-vitamin D2 + NADP+ + H2O
show the reaction diagram
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?
vitamin D2 + O2 + NADPH + H+
25-hydroxyvitamin D2 + NADP+ + H2O
show the reaction diagram
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-
-
?
vitamin D3 + O2 + NADPH + H+
25-hydroxy-vitamin D3 + NADP+ + H2O
show the reaction diagram
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?
vitamin D3 + O2 + NADPH + H+
25-hydroxyvitamin D3 + NADP+ + H2O
show the reaction diagram
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
calciferol + O2 + [reduced NADPH-hemoprotein reductase]
25-hydroxy-vitamin D2 + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
Q6VVX0
enzyme CYP2R1 hydroxylates vitamin D2 at position C-25 position
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-
?
calciol + O2 + [reduced NADPH-hemoprotein reductase]
calcidiol + [oxidized NADPH-hemoprotein reductase] + H2O
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Iron
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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 hide
LITERATURE
IMAGE
0.0158
1alpha-hydroxyvitamin D2
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pH 7.4, 37°C
0.0044 - 0.0113
1alpha-hydroxyvitamin D3
0.00045 - 0.002
vitamin D2
0.0044 - 0.0077
vitamin D3
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.02
1alpha-hydroxyvitamin D2
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pH 7.4, 37°C
0.0075 - 0.037
1alpha-hydroxyvitamin D3
0.0027 - 0.017
vitamin D2
0.0015 - 0.008
vitamin D3
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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high levels of CYP2R1 expression compared to healthy adjacent tissue
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
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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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expresion in Escherichia coli
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expression in Escherichia coli
expression in Saccharomyces cerevisiae
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functional recombinant expression of human CYP2R1 in Saccharomyces cerevisiae
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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
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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
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A326G
about 90% loss of activity with all substrates tested
L99P
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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
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine