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 06-MAR-2013, entry version 89. DE RecName: Full=Vitamin D 25-hydroxylase; DE EC=1.14.13.159; DE AltName: Full=Cytochrome P450 2R1; GN Name=CYP2R1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY. RX MEDLINE=22863117; 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, AND RP BIOPHYSICOCHEMICAL PROPERTIES. 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 RT project: 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 RP VITAMIN D3 AND HEME, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL RP PROPERTIES, AND SUBUNIT. 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 RP HEME; 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 RT D2 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). CC -!- FUNCTION: Has a D-25-hydroxylase activity on both forms of vitamin CC D, vitamin D(2) and D(3). CC -!- CATALYTIC ACTIVITY: Calciol + O(2) + NADPH = calcidiol + NADP(+) CC H(2)O. CC -!- COFACTOR: Heme group (By similarity). CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.67 uM for vitamin D(2); CC KM=0.45 uM for vitamin D(3); CC -!- SUBUNIT: Homodimer. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral CC membrane protein. Microsome membrane; Peripheral membrane protein. CC -!- DISEASE: Defects in CYP2R1 are the cause of rickets vitamin D- CC dependent type 1B (VDDR1B) [MIM:600081]; also known as CC pseudovitamin D(3) deficiency rickets due to 25-hydroxylase CC deficiency. A disorder caused by a selective deficiency of the CC active form of vitamin D (1,25-dihydroxyvitamin D3) and resulting CC in defective bone mineralization and clinical features of rickets. CC The patients sera have low calcium concentrations, low phosphate CC concentrations, elevated alkaline phosphatase activityand low CC levels of 25-hydroxyvitamin D. CC -!- SIMILARITY: Belongs to the cytochrome P450 family. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 IPI; IPI00409700; -. DR RefSeq; NP_078790.2; NM_024514.4. DR UniGene; Hs.371427; -. 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 ProteinModelPortal; Q6VVX0; -. DR SMR; Q6VVX0; 49-501. DR STRING; Q6VVX0; -. DR DMDM; 62286619; -. DR PRIDE; Q6VVX0; -. DR Ensembl; ENST00000334636; ENSP00000334592; ENSG00000186104. DR Ensembl; ENST00000572354; ENSP00000461178; ENSG00000262968. DR GeneID; 120227; -. DR KEGG; hsa:120227; -. DR UCSC; uc001mlp.3; human. DR CTD; 120227; -. DR GeneCards; GC11M014856; -. DR HGNC; HGNC:20580; CYP2R1. DR HPA; HPA042949; -. DR MIM; 600081; phenotype. DR MIM; 608713; gene. DR neXtProt; NX_Q6VVX0; -. DR Orphanet; 289157; Hypocalcemic vitamin D dependent rickets. DR PharmGKB; PA134986407; -. DR eggNOG; COG2124; -. DR HOGENOM; HOG000036991; -. DR HOVERGEN; HBG015789; -. DR InParanoid; Q6VVX0; -. DR KO; K07419; -. DR OMA; WRDPEVF; -. DR OrthoDB; EOG40P46M; -. DR PhylomeDB; Q6VVX0; -. DR BioCyc; MetaCyc:HS17721-MONOMER; -. DR Reactome; REACT_111217; Metabolism. DR Reactome; REACT_15493; Steroid hormones. DR SABIO-RK; Q6VVX0; -. DR DrugBank; DB00169; Cholecalciferol. DR DrugBank; DB00153; Ergocalciferol. DR EvolutionaryTrace; Q6VVX0; -. DR GenomeRNAi; 120227; -. DR NextBio; 80549; -. DR ArrayExpress; Q6VVX0; -. DR Bgee; Q6VVX0; -. DR CleanEx; HS_CYP2R1; -. DR Genevestigator; Q6VVX0; -. DR GermOnline; ENSG00000186104; Homo sapiens. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0009055; F:electron carrier activity; IEA:InterPro. DR GO; GO:0020037; F:heme binding; IEA:InterPro. DR GO; GO:0005506; F:iron ion binding; IEA:InterPro. DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW. DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro. DR GO; GO:0030343; F:vitamin D3 25-hydroxylase activity; IEA:Compara. DR GO; GO:0010164; P:response to cesium ion; IEA:Compara. DR GO; GO:0010212; P:response to ionizing radiation; IEA:Compara. DR GO; GO:0042359; P:vitamin D metabolic process; TAS:Reactome. DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome. 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 Pfam; PF00067; p450; 1. DR PRINTS; PR00463; EP450I. DR PRINTS; PR00385; P450. DR SUPFAM; SSF48264; Cytochrome_P450; 1. DR PROSITE; PS00086; CYTOCHROME_P450; 1. PE 1: Evidence at protein level; KW 3D-structure; Complete proteome; Disease mutation; KW Endoplasmic reticulum; Heme; Iron; Membrane; Metal-binding; Microsome; KW Monooxygenase; NADP; Oxidoreductase; Reference proteome. FT CHAIN 1 501 Vitamin D 25-hydroxylase. FT /FTId=PRO_0000051778. FT METAL 448 448 Iron (heme axial ligand). FT BINDING 250 250 Substrate; via carbonyl oxygen. FT VARIANT 99 99 L -> P (in VDDR1B; complete loss of FT activity; dbSNP:rs61495246). FT /FTId=VAR_021534. FT TURN 47 49 FT HELIX 52 57 FT HELIX 62 73 FT STRAND 75 81 FT STRAND 84 91 FT HELIX 92 99 FT TURN 100 106 FT HELIX 113 119 FT HELIX 131 146 FT TURN 147 150 FT HELIX 154 170 FT TURN 171 174 FT HELIX 180 196 FT HELIX 205 220 FT HELIX 224 231 FT HELIX 233 237 FT STRAND 239 241 FT HELIX 242 265 FT HELIX 276 286 FT TURN 287 289 FT HELIX 297 328 FT HELIX 330 343 FT STRAND 346 348 FT HELIX 352 357 FT HELIX 359 372 FT STRAND 387 389 FT STRAND 392 394 FT STRAND 399 403 FT HELIX 404 408 FT TURN 411 413 FT STRAND 414 416 FT HELIX 422 425 FT HELIX 451 468 FT STRAND 469 472 FT HELIX 474 476 FT STRAND 485 488 FT STRAND 496 500 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 //