Q6VVX0 (CP2R1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Vitamin D 25-hydroxylase
EC=1.14.13.15

Alternative name(s):
Cytochrome P450 2R1

Gene names

Name:

CYP2R1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	501 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Has a D-25-hydroxylase activity on both forms of vitamin D, vitamin D2 and D3. Ref.1 Ref.2 Ref.5
Catalytic activity	5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol + NADPH + O2 = (25R)-5-beta-cholestane-3-alpha,7-alpha,12-alpha,26-tetraol + NADP+ + H2O.
Cofactor	Heme group By similarity.
Subunit structure	Homodimer. Ref.5
Subcellular location	Endoplasmic reticulum membrane; Peripheral membrane protein. Microsome membrane; Peripheral membrane protein.
Involvement in disease	Defects in CYP2R1 are the cause of rickets vitamin D-dependent type 1B (VDDR1B) [MIM:600081]; also known as pseudovitamin D3 deficiency rickets due to 25-hydroxylase deficiency. A disorder caused by a selective deficiency of the active form of vitamin D (1,25-dihydroxyvitamin D3) and resulting in defective bone mineralization and clinical features of rickets. The patients sera have low calcium concentrations, low phosphate concentrations, elevated alkaline phosphatase activityand low levels of 25-hydroxyvitamin D. Ref.7
Sequence similarities	Belongs to the cytochrome P450 family.
Biophysicochemical properties	Kinetic parameters: KM=0.67 µM for vitamin D2 Ref.2 Ref.5 KM=0.45 µM for vitamin D3

Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane Microsome
Disease	Disease mutation
Ligand	Heme Iron Metal-binding NADP
Molecular function	Monooxygenase Oxidoreductase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	vitamin D metabolic process Traceable author statement. Source: Reactome xenobiotic metabolic process Traceable author statement. Source: Reactome
Cellular component	endoplasmic reticulum membrane Traceable author statement. Source: Reactome microsome Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	cholestanetriol 26-monooxygenase activity Inferred from electronic annotation. Source: EC electron carrier activity Inferred from electronic annotation. Source: InterPro heme binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 501

501

Vitamin D 25-hydroxylase

PRO_0000051778

Sites

Metal binding

448

1

Iron (heme axial ligand)

Binding site

250

1

Substrate; via carbonyl oxygen

Natural variations

Natural variant

99

1

L → P in VDDR1B; complete loss of activity. Ref.7
Corresponds to variant rs61495246 [ dbSNP | Ensembl ].

VAR_021534

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

501

Helix Strand Turn

Details...

Turn

47 – 49

3

Helix

52 – 57

6

Helix

62 – 73

12

Beta strand

75 – 81

7

Beta strand

84 – 89

6

Helix

91 – 99

9

Turn

100 – 106

7

Helix

113 – 119

7

Helix

131 – 146

16

Turn

147 – 150

4

Helix

154 – 171

18

Turn

172 – 174

3

Helix

180 – 196

17

Helix

205 – 220

16

Helix

224 – 231

8

Helix

233 – 237

5

Helix

242 – 265

24

Helix

276 – 286

11

Helix

297 – 328

32

Helix

330 – 343

14

Turn

344 – 347

4

Helix

352 – 357

6

Helix

359 – 372

14

Beta strand

387 – 389

3

Beta strand

392 – 394

3

Beta strand

399 – 402

4

Helix

404 – 408

5

Turn

411 – 413

3

Beta strand

414 – 416

3

Helix

422 – 425

4

Helix

451 – 468

18

Beta strand

469 – 472

4

Helix

474 – 476

3

Beta strand

486 – 488

3

Beta strand

496 – 500

5

Sequences

	Sequence		Length	Mass (Da)
	Q6VVX0 [UniParc]. Last modified July 5, 2004. Version 1. Checksum: F05E5245C580C29E	FASTA	501	57,359
	10 20 30 40 50 60 MWKLWRAEEG AAALGGALFL LLFALGVRQL LKQRRPMGFP PGPPGLPFIG NIYSLAASSE 70 80 90 100 110 120 LPHVYMRKQS QVYGEIFSLD LGGISTVVLN GYDVVKECLV HQSEIFADRP CLPLFMKMTK 130 140 150 160 170 180 MGGLLNSRYG RGWVDHRRLA VNSFRYFGYG QKSFESKILE ETKFFNDAIE TYKGRPFDFK 190 200 210 220 230 240 QLITNAVSNI TNLIIFGERF TYEDTDFQHM IELFSENVEL AASASVFLYN AFPWIGILPF 250 260 270 280 290 300 GKHQQLFRNA AVVYDFLSRL IEKASVNRKP QLPQHFVDAY LDEMDQGKND PSSTFSKENL 310 320 330 340 350 360 IFSVGELIIA GTETTTNVLR WAILFMALYP NIQGQVQKEI DLIMGPNGKP SWDDKCKMPY 370 380 390 400 410 420 TEAVLHEVLR FCNIVPLGIF HATSEDAVVR GYSIPKGTTV ITNLYSVHFD EKYWRDPEVF 430 440 450 460 470 480 HPERFLDSSG YFAKKEALVP FSLGRRHCLG EHLARMEMFL FFTALLQRFH LHFPHELVPD 490 500 LKPRLGMTLQ PQPYLICAER R

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxylase." Cheng J.B., Motola D.L., Mangelsdorf D.J., Russell D.W. J. Biol. Chem. 278:38084-38093(2003) [PubMed: 12867411] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]	"Metabolism of vitamin D by human microsomal CYP2R1." Shinkyo R., Sakaki T., Kamakura M., Ohta M., Inouye K. Biochem. Biophys. Res. Commun. 324:451-457(2004) [PubMed: 15465040] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES.
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Liver.
[4]	"Human CYP2R1 gene 5'-flanking region." Tsuruga E., Bell N.H., Reddy S.V. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-8.
[5]	"Structural analysis of CYP2R1 in complex with vitamin D3." Strushkevich N., Usanov S.A., Plotnikov A.N., Jones G., Park H.-W. J. Mol. Biol. 380:95-106(2008) [PubMed: 18511070] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 32-501 IN COMPLEX WITH VITAMIN D3 AND HEME, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT.
[6]	"Crystal structure of CYP2R1 in complexes with 1-alpha-hydroxy-vitamin D2 and with vitamin D2." Structural genomics consortium (SGC) Submitted (FEB-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.72 ANGSTROMS) OF 32-501 IN COMPLEXES WITH HEME; VITAMIN D2 AND 1-ALPHA-HYDROXY-VITAMIN D2.
[7]	"Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase." Cheng J.B., Levine M.A., Bell N.H., Mangelsdorf D.J., Russell D.W. Proc. Natl. Acad. Sci. U.S.A. 101:7711-7715(2004) [PubMed: 15128933] [Abstract] Cited for: VARIANT VDDR1B PRO-99.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AY323817 mRNA. Translation: AAQ23114.1.
BC104907 mRNA. Translation: AAI04908.1.
BC104909 mRNA. Translation: AAI04910.1.
AY800276 Genomic DNA. Translation: AAV65814.1.

IPI

IPI00409700.

RefSeq

NP_078790.2. NM_024514.4.

UniGene

Hs.371427.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3C6G	X-ray	2.80	A/B	32-501	[»]
3CZH	X-ray	2.30	A/B	32-501	[»]
3DL9	X-ray	2.72	A/B	32-501	[»]

ProteinModelPortal

Q6VVX0.

SMR

Q6VVX0. Positions 49-501.

ModBase

Search...

Protein-protein interaction databases

STRING

Q6VVX0.

Polymorphism databases

DMDM

62286619.

Proteomic databases

PRIDE

Q6VVX0.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000334636; ENSP00000334592; ENSG00000186104.

GeneID

120227.

KEGG

hsa:120227.

UCSC

uc001mlp.1. human.

Organism-specific databases

CTD

120227.

GeneCards

GC11M014856.

H-InvDB

HIX0009468.

HGNC

HGNC:20580. CYP2R1.

MIM

600081. phenotype.
608713. gene.

neXtProt

NX_Q6VVX0.

Orphanet

93160. Hypocalcemic rickets.

PharmGKB

PA134986407.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04176.

GeneTree

ENSGT00560000076621.

HOGENOM

HBG749920.

HOVERGEN

HBG015789.

InParanoid

Q6VVX0.

OMA

SFRYFGY.

OrthoDB

EOG40P46M.

PhylomeDB

Q6VVX0.

Enzyme and pathway databases

BioCyc

MetaCyc:MONOMER-14353.

Reactome

REACT_111217. Metabolism.
REACT_15493. Steroid hormones.
REACT_22258. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

Q6VVX0.

Bgee

Q6VVX0.

CleanEx

HS_CYP2R1.

Genevestigator

Q6VVX0.

GermOnline

ENSG00000186104. Homo sapiens.

Family and domain databases

InterPro

IPR001128. Cyt_P450.
IPR017972. Cyt_P450_CS.
IPR002401. Cyt_P450_E_grp-I.
[Graphical view]

Gene3D

G3DSA:1.10.630.10. Cyt_P450. 1 hit.

KO

K07419.

Pfam

PF00067. p450. 1 hit.
[Graphical view]

PRINTS

PR00463. EP450I.
PR00385. P450.

SUPFAM

SSF48264. Cytochrome_P450. 1 hit.

PROSITE

PS00086. CYTOCHROME_P450. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00169. Cholecalciferol.
DB00153. Ergocalciferol.

NextBio

80549.

SOURCE

Search...

Entry information

Entry name

CP2R1_HUMAN

Accession

Primary (citable) accession number: Q6VVX0
Secondary accession number(s): Q2M3H3, Q5RT65

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 29, 2005
Last sequence update:	July 5, 2004
Last modified:	January 25, 2012
This is version 78 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.