CP2R1_HUMAN
ID CP2R1_HUMAN Reviewed; 501 AA.
AC Q6VVX0; Q2M3H3; Q5RT65;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Vitamin D 25-hydroxylase {ECO:0000303|PubMed:12867411};
DE EC=1.14.14.24 {ECO:0000269|PubMed:12867411, ECO:0000269|PubMed:15465040, ECO:0000269|PubMed:18511070};
DE AltName: Full=Cytochrome P450 2R1;
DE Flags: Precursor;
GN Name=CYP2R1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=12867411; DOI=10.1074/jbc.m307028200;
RA Cheng J.B., Motola D.L., Mangelsdorf D.J., Russell D.W.;
RT "De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-
RT hydroxylase.";
RL J. Biol. Chem. 278:38084-38093(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY, AND SUBCELLULAR LOCATION.
RX PubMed=15465040; DOI=10.1016/j.bbrc.2004.09.073;
RA Shinkyo R., Sakaki T., Kamakura M., Ohta M., Inouye K.;
RT "Metabolism of vitamin D by human microsomal CYP2R1.";
RL Biochem. Biophys. Res. Commun. 324:451-457(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-8.
RA Tsuruga E., Bell N.H., Reddy S.V.;
RT "Human CYP2R1 gene 5'-flanking region.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 32-501 IN COMPLEX WITH VITAMIN D3
RP AND HEME, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP SUBUNIT, AND PATHWAY.
RX PubMed=18511070; DOI=10.1016/j.jmb.2008.03.065;
RA Strushkevich N., Usanov S.A., Plotnikov A.N., Jones G., Park H.-W.;
RT "Structural analysis of CYP2R1 in complex with vitamin D3.";
RL J. Mol. Biol. 380:95-106(2008).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.72 ANGSTROMS) OF 32-501 IN COMPLEXES WITH HEME;
RP VITAMIN D2 AND 1-ALPHA-HYDROXY-VITAMIN D2.
RG Structural genomics consortium (SGC);
RT "Crystal structure of CYP2R1 in complexes with 1-alpha-hydroxy-vitamin D2
RT and with vitamin D2.";
RL Submitted (FEB-2009) to the PDB data bank.
RN [7]
RP VARIANT VDDR1B PRO-99.
RX PubMed=15128933; DOI=10.1073/pnas.0402490101;
RA Cheng J.B., Levine M.A., Bell N.H., Mangelsdorf D.J., Russell D.W.;
RT "Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-
RT hydroxylase.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:7711-7715(2004).
RN [8]
RP VARIANT VDDR1B PRO-99, VARIANT ASN-242, CHARACTERIZATION OF VARIANT VDDR1B
RP PRO-99, AND CHARACTERIZATION OF VARIANT ASN-242.
RX PubMed=25942481; DOI=10.1210/jc.2015-1746;
RA Thacher T.D., Fischer P.R., Singh R.J., Roizen J., Levine M.A.;
RT "CYP2R1 mutations impair generation of 25-hydroxyvitamin D and cause an
RT atypical form of vitamin D deficiency.";
RL J. Clin. Endocrinol. Metab. 100:E1005-1013(2015).
CC -!- FUNCTION: A cytochrome P450 monooxygenase involved in activation of
CC vitamin D precursors. Catalyzes hydroxylation at C-25 of both forms of
CC vitamin D, vitamin D(2) and D(3) (calciol) (PubMed:12867411,
CC PubMed:15465040, PubMed:18511070). Can metabolize vitamin D
CC analogs/prodrugs 1alpha-hydroxyvitamin D(2) (doxercalciferol) and
CC 1alpha-hydroxyvitamin D(3) (alfacalcidol) forming 25-hydroxy
CC derivatives (PubMed:15465040, PubMed:18511070). Mechanistically, uses
CC molecular oxygen inserting one oxygen atom into a substrate, and
CC reducing the second into a water molecule, with two electrons provided
CC by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein
CC reductase) (PubMed:12867411, PubMed:15465040, PubMed:18511070).
CC {ECO:0000269|PubMed:12867411, ECO:0000269|PubMed:15465040,
CC ECO:0000269|PubMed:18511070}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=calciol + O2 + reduced [NADPH--hemoprotein reductase] =
CC calcidiol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:32903, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:17933, ChEBI:CHEBI:28940, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; EC=1.14.14.24;
CC Evidence={ECO:0000269|PubMed:12867411, ECO:0000269|PubMed:15465040,
CC ECO:0000269|PubMed:18511070};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32904;
CC Evidence={ECO:0000305|PubMed:15465040};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + vitamin D2 = 25-
CC hydroxyvitamin D2 + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:46580, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:28934, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:86319; Evidence={ECO:0000269|PubMed:15465040,
CC ECO:0000269|PubMed:18511070};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46581;
CC Evidence={ECO:0000305|PubMed:15465040};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1alpha-hydroxyvitamin D2 + O2 + reduced [NADPH--hemoprotein
CC reductase] = 1alpha,25-dihydroxyvitamin D2 + H(+) + H2O + oxidized
CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:46584, Rhea:RHEA-
CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:4712,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:86320;
CC Evidence={ECO:0000269|PubMed:15465040, ECO:0000269|PubMed:18511070};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46585;
CC Evidence={ECO:0000305|PubMed:15465040};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=alfacalcidol + O2 + reduced [NADPH--hemoprotein reductase] =
CC calcitriol + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:49272, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:17823, ChEBI:CHEBI:31186, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:15465040};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49273;
CC Evidence={ECO:0000305|PubMed:15465040};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:18511070};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.67 uM for vitamin D(2) {ECO:0000269|PubMed:15465040};
CC KM=0.45 uM for vitamin D(3) {ECO:0000269|PubMed:15465040};
CC KM=4.4 uM for vitamin D(3) {ECO:0000269|PubMed:18511070};
CC KM=15.8 uM for 1alpha-hydroxyvitamin D(2)
CC {ECO:0000269|PubMed:18511070};
CC KM=11.3 uM for 1alpha-hydroxyvitamin D(3)
CC {ECO:0000269|PubMed:18511070};
CC -!- PATHWAY: Hormone biosynthesis; vitamin D biosynthesis.
CC {ECO:0000305|PubMed:15465040, ECO:0000305|PubMed:18511070}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:18511070}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000305|PubMed:15465040}; Peripheral membrane protein. Microsome
CC membrane {ECO:0000305|PubMed:15465040}; Peripheral membrane protein.
CC -!- DISEASE: Rickets vitamin D-dependent 1B (VDDR1B) [MIM:600081]: An
CC autosomal recessive disorder caused by a selective deficiency of the
CC active form of vitamin D (1,25-dihydroxyvitamin D3) and resulting in
CC defective bone mineralization and clinical features of rickets. The
CC patients sera have low calcium concentrations, low phosphate
CC concentrations, elevated alkaline phosphatase activity and low levels
CC of 25-hydroxyvitamin D. {ECO:0000269|PubMed:15128933,
CC ECO:0000269|PubMed:25942481}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AY323817; AAQ23114.1; -; mRNA.
DR EMBL; BC104907; AAI04908.1; -; mRNA.
DR EMBL; BC104909; AAI04910.1; -; mRNA.
DR EMBL; AY800276; AAV65814.1; -; Genomic_DNA.
DR CCDS; CCDS7818.1; -.
DR RefSeq; NP_078790.2; NM_024514.4.
DR PDB; 3C6G; X-ray; 2.80 A; A/B=32-501.
DR PDB; 3CZH; X-ray; 2.30 A; A/B=32-501.
DR PDB; 3DL9; X-ray; 2.72 A; A/B=32-501.
DR PDBsum; 3C6G; -.
DR PDBsum; 3CZH; -.
DR PDBsum; 3DL9; -.
DR AlphaFoldDB; Q6VVX0; -.
DR SMR; Q6VVX0; -.
DR STRING; 9606.ENSP00000334592; -.
DR BindingDB; Q6VVX0; -.
DR ChEMBL; CHEMBL4523986; -.
DR DrugBank; DB00169; Cholecalciferol.
DR DrugBank; DB00153; Ergocalciferol.
DR DrugBank; DB11094; Vitamin D.
DR DrugCentral; Q6VVX0; -.
DR SwissLipids; SLP:000001264; -.
DR iPTMnet; Q6VVX0; -.
DR PhosphoSitePlus; Q6VVX0; -.
DR BioMuta; CYP2R1; -.
DR DMDM; 62286619; -.
DR jPOST; Q6VVX0; -.
DR MassIVE; Q6VVX0; -.
DR PaxDb; Q6VVX0; -.
DR PeptideAtlas; Q6VVX0; -.
DR PRIDE; Q6VVX0; -.
DR ProteomicsDB; 67733; -.
DR Antibodypedia; 24708; 223 antibodies from 28 providers.
DR DNASU; 120227; -.
DR Ensembl; ENST00000334636.10; ENSP00000334592.5; ENSG00000186104.11.
DR GeneID; 120227; -.
DR KEGG; hsa:120227; -.
DR MANE-Select; ENST00000334636.10; ENSP00000334592.5; NM_024514.5; NP_078790.2.
DR UCSC; uc001mlr.4; human.
DR CTD; 120227; -.
DR DisGeNET; 120227; -.
DR GeneCards; CYP2R1; -.
DR HGNC; HGNC:20580; CYP2R1.
DR HPA; ENSG00000186104; Low tissue specificity.
DR MalaCards; CYP2R1; -.
DR MIM; 600081; phenotype.
DR MIM; 608713; gene.
DR neXtProt; NX_Q6VVX0; -.
DR OpenTargets; ENSG00000186104; -.
DR Orphanet; 289157; Hypocalcemic vitamin D-dependent rickets.
DR PharmGKB; PA134986407; -.
DR VEuPathDB; HostDB:ENSG00000186104; -.
DR eggNOG; KOG0156; Eukaryota.
DR GeneTree; ENSGT00940000158305; -.
DR HOGENOM; CLU_001570_22_0_1; -.
DR InParanoid; Q6VVX0; -.
DR OMA; AEINQTG; -.
DR OrthoDB; 702827at2759; -.
DR PhylomeDB; Q6VVX0; -.
DR TreeFam; TF352043; -.
DR BioCyc; MetaCyc:HS17721-MON; -.
DR BRENDA; 1.14.14.24; 2681.
DR PathwayCommons; Q6VVX0; -.
DR Reactome; R-HSA-196791; Vitamin D (calciferol) metabolism.
DR Reactome; R-HSA-211916; Vitamins.
DR Reactome; R-HSA-5579027; Defective CYP27B1 causes VDDR1B.
DR SABIO-RK; Q6VVX0; -.
DR UniPathway; UPA00954; -.
DR BioGRID-ORCS; 120227; 13 hits in 1076 CRISPR screens.
DR ChiTaRS; CYP2R1; human.
DR EvolutionaryTrace; Q6VVX0; -.
DR GeneWiki; CYP2R1; -.
DR GenomeRNAi; 120227; -.
DR Pharos; Q6VVX0; Tbio.
DR PRO; PR:Q6VVX0; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q6VVX0; protein.
DR Bgee; ENSG00000186104; Expressed in sperm and 164 other tissues.
DR ExpressionAtlas; Q6VVX0; baseline and differential.
DR Genevisible; Q6VVX0; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:1902271; F:D3 vitamins binding; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR GO; GO:0005506; F:iron ion binding; IDA:UniProtKB.
DR GO; GO:0016712; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen; IBA:GO_Central.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0008395; F:steroid hydroxylase activity; IBA:GO_Central.
DR GO; GO:0030343; F:vitamin D3 25-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0036378; P:calcitriol biosynthetic process from calciol; IDA:UniProtKB.
DR GO; GO:0006082; P:organic acid metabolic process; IBA:GO_Central.
DR GO; GO:0042359; P:vitamin D metabolic process; TAS:Reactome.
DR GO; GO:0006766; P:vitamin metabolic process; TAS:Reactome.
DR GO; GO:0006805; P:xenobiotic metabolic process; IBA:GO_Central.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002401; Cyt_P450_E_grp-I.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disease variant; Endoplasmic reticulum; Heme; Iron;
KW Lipid metabolism; Membrane; Metal-binding; Microsome; Monooxygenase;
KW Oxidoreductase; Reference proteome; Signal.
FT SIGNAL 1..26
FT /evidence="ECO:0000255"
FT CHAIN 27..501
FT /note="Vitamin D 25-hydroxylase"
FT /evidence="ECO:0000255"
FT /id="PRO_0000051778"
FT BINDING 250
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:18511070"
FT BINDING 448
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000269|PubMed:18511070"
FT VARIANT 99
FT /note="L -> P (in VDDR1B; complete loss of activity;
FT dbSNP:rs61495246)"
FT /evidence="ECO:0000269|PubMed:15128933,
FT ECO:0000269|PubMed:25942481"
FT /id="VAR_021534"
FT VARIANT 242
FT /note="K -> N (reduces 25-hydroxylase activity)"
FT /evidence="ECO:0000269|PubMed:25942481"
FT /id="VAR_075532"
FT TURN 47..49
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 52..57
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 62..73
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 75..81
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 84..91
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 92..99
FT /evidence="ECO:0007829|PDB:3CZH"
FT TURN 100..106
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 113..119
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 131..146
FT /evidence="ECO:0007829|PDB:3CZH"
FT TURN 147..150
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 154..170
FT /evidence="ECO:0007829|PDB:3CZH"
FT TURN 171..174
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 180..196
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 205..220
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 224..231
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 233..237
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 239..241
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 242..265
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 276..286
FT /evidence="ECO:0007829|PDB:3CZH"
FT TURN 287..289
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 297..328
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 330..343
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 346..348
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 352..357
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 359..372
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 387..389
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 392..394
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 399..403
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 404..408
FT /evidence="ECO:0007829|PDB:3CZH"
FT TURN 411..413
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 414..416
FT /evidence="ECO:0007829|PDB:3C6G"
FT HELIX 422..425
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 451..468
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 469..472
FT /evidence="ECO:0007829|PDB:3CZH"
FT HELIX 474..476
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 485..488
FT /evidence="ECO:0007829|PDB:3CZH"
FT STRAND 496..500
FT /evidence="ECO:0007829|PDB:3CZH"
SQ SEQUENCE 501 AA; 57359 MW; F05E5245C580C29E CRC64;
MWKLWRAEEG AAALGGALFL LLFALGVRQL LKQRRPMGFP PGPPGLPFIG NIYSLAASSE
LPHVYMRKQS QVYGEIFSLD LGGISTVVLN GYDVVKECLV HQSEIFADRP CLPLFMKMTK
MGGLLNSRYG RGWVDHRRLA VNSFRYFGYG QKSFESKILE ETKFFNDAIE TYKGRPFDFK
QLITNAVSNI TNLIIFGERF TYEDTDFQHM IELFSENVEL AASASVFLYN AFPWIGILPF
GKHQQLFRNA AVVYDFLSRL IEKASVNRKP QLPQHFVDAY LDEMDQGKND PSSTFSKENL
IFSVGELIIA GTETTTNVLR WAILFMALYP NIQGQVQKEI DLIMGPNGKP SWDDKCKMPY
TEAVLHEVLR FCNIVPLGIF HATSEDAVVR GYSIPKGTTV ITNLYSVHFD EKYWRDPEVF
HPERFLDSSG YFAKKEALVP FSLGRRHCLG EHLARMEMFL FFTALLQRFH LHFPHELVPD
LKPRLGMTLQ PQPYLICAER R
