NADPH--cytochrome P450 reductase - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot P16435 (NCPR_HUMAN)

Last modified June 16, 2009. Version 117. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    NADPH--cytochrome P450 reductase
      Short name=CPR
      Short name=P450R
    EC=1.6.2.4

Gene names

Name:	POR
Synonyms:	CYPOR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	677 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5.
Catalytic activity	NADPH + n oxidized hemoprotein = NADP⁺ + n reduced hemoprotein.
Cofactor	FAD. FMN.
Subcellular location	Endoplasmic reticulum membrane; Peripheral membrane protein. Note: Anchored to the ER membrane by its N-terminal hydrophobic region.
Involvement in disease	Defects in POR are the cause of adrenal hyperplasia variant type (AHV) [MIM:201750]; also known as Antley-Bixler syndrome-like phenotype with disordered steroidogenesis. AHV is a rare variant of congenital adrenal hyperplasia. It is an autosomal recessive disorder with apparent combined P450C17 and P450C21 deficiency. Affected girls are born with ambiguous genitalia, but their circulating androgens are low and virilization does not progress. Conversely, affected boys are sometimes born undermasculinized. Boys and girls can also present with bone malformations, in some cases resembling the pattern seen in patients with Antley-Bixler syndrome. Ref.9 Ref.10 Ref.11 Ref.12 Defects in POR are a cause of isolated disordered steroidogenesis (IDS) [MIM:201750]. Ref.12
Sequence similarities	In the C-terminal section; belongs to the flavoprotein pyridine nucleotide cytochrome reductase family. Contains 1 FAD-binding FR-type domain. Contains 1 flavodoxin-like domain.

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Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Polymorphism
Disease	Congenital adrenal hyperplasia Disease mutation
Ligand	FAD FMN Flavoprotein NADP
Molecular function	Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	oxidation reduction Ref.8 Traceable author statement. Source: UniProtKB
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	FMN binding Inferred from electronic annotation. Source: InterPro NADPH-hemoprotein reductase activity Ref.6 Ref.8 Traceable author statement. Source: UniProtKB electron carrier activity Inferred from electronic annotation. Source: InterPro iron ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

Removed Ref.6

Chain

2 – 677

676

NADPH--cytochrome P450 reductase

PRO_0000167596

Regions

Domain

80 – 224

145

Flavodoxin-like

Domain

279 – 521

243

FAD-binding FR-type

Nucleotide binding

170 – 201

FMN By similarity

Nucleotide binding

314 – 325

FAD By similarity

Nucleotide binding

451 – 461

FAD By similarity

Nucleotide binding

529 – 547

NADP By similarity

Nucleotide binding

623 – 639

NADP By similarity

Amino acid modifications

Modified residue

N-acetylglycine

Modified residue

575

Phosphotyrosine By similarity

Natural variations

Natural variant

178

Y → D in AHV; complete loss of activity. Ref.11

VAR_021154

Natural variant

225

P → L Ref.4 Ref.5

VAR_047885

Natural variant

252

D → N Ref.4

VAR_047886

Natural variant

284

A → P in AHV; significant reduction of activity. Ref.11 Ref.12

VAR_021155

Natural variant

454

R → H in AHV; significant reduction of activity. Ref.9 Ref.10 Ref.11 Ref.12

VAR_021156

Natural variant

489

V → E in AHV; significant reduction of activity. Ref.12

VAR_021157

Natural variant

500

A → V: dbSNP rs1057868. Ref.10 Ref.4 Ref.5 Ref.1

VAR_004617

Natural variant

551

R → Q

VAR_004618

Natural variant

566

C → Y in IDS and AHV; significant reduction of activity.

VAR_021158

Natural variant

575

Y → C in AHV; with abnormal genitalia. Ref.10

VAR_021159

Natural variant

605

V → F in IDS; significant reduction of activity. Ref.12

VAR_021160

Natural variant

609 – 617

LKQDREHLW → R in AHV.

VAR_021161

Experimental info

Sequence conflict

405

M → L in BAB18572. Ref.3

Sequence conflict

518

F → L in AAB21814. Ref.1

Sequence conflict

518

F → L in BAB18572. Ref.3

Sequence conflict

537 – 538

VA → WH in AAB21814. Ref.1

Secondary structure

677

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P16435-1 [UniParc].

Last modified January 23, 2007. Version 2.
Checksum: 2F7D4B9CDFDF5A74
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FASTA

677

76,690

        10         20         30         40         50         60 
MGDSHVDTSS TVSEAVAEEV SLFSMTDMIL FSLIVGLLTY WFLFRKKKEE VPEFTKIQTL 

        70         80         90        100        110        120 
TSSVRESSFV EKMKKTGRNI IVFYGSQTGT AEEFANRLSK DAHRYGMRGM SADPEEYDLA 

       130        140        150        160        170        180 
DLSSLPEIDN ALVVFCMATY GEGDPTDNAQ DFYDWLQETD VDLSGVKFAV FGLGNKTYEH 

       190        200        210        220        230        240 
FNAMGKYVDK RLEQLGAQRI FELGLGDDDG NLEEDFITWR EQFWPAVCEH FGVEATGEES 

       250        260        270        280        290        300 
SIRQYELVVH TDIDAAKVYM GEMGRLKSYE NQKPPFDAKN PFLAAVTTNR KLNQGTERHL 

       310        320        330        340        350        360 
MHLELDISDS KIRYESGDHV AVYPANDSAL VNQLGKILGA DLDVVMSLNN LDEESNKKHP 

       370        380        390        400        410        420 
FPCPTSYRTA LTYYLDITNP PRTNVLYELA QYASEPSEQE LLRKMASSSG EGKELYLSWV 

       430        440        450        460        470        480 
VEARRHILAI LQDCPSLRPP IDHLCELLPR LQARYYSIAS SSKVHPNSVH ICAVVVEYET 

       490        500        510        520        530        540 
KAGRINKGVA TNWLRAKEPA GENGGRALVP MFVRKSQFRL PFKATTPVIM VGPGTGVAPF 

       550        560        570        580        590        600 
IGFIQERAWL RQQGKEVGET LLYYGCRRSD EDYLYREELA QFHRDGALTQ LNVAFSREQS 

       610        620        630        640        650        660 
HKVYVQHLLK QDREHLWKLI EGGAHIYVCG DARNMARDVQ NTFYDIVAEL GAMEHAQAVD 

       670 
YIKKLMTKGR YSLDVWS

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Quantification of cytochrome P450 reductase gene expression in human tissues." Shephard E.A., Palmer C.N., Segall H.J., Phillips I.R. Arch. Biochem. Biophys. 294:168-172(1992) [PubMed: 1550342] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-500.
[2]	"Polymorphism of human CYPOR: expression of new allele." Czerwinski M., Sahni M., Madan A., Parkinson A. Submitted (APR-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[3]	"cDNA cloning and characterization of NADPH-cytochrome P-450 reductase in human HL-60 cell." Murakami H.O., Ogawa H., Nisimoto Y. Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	NIEHS SNPs program Submitted (MAY-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LEU-225; ASN-252 AND VAL-500.
[5]	"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], VARIANTS LEU-225 AND VAL-500. Tissue: Lung.
[6]	"Structural and functional analysis of NADPH-cytochrome P-450 reductase from human liver: complete sequence of human enzyme and NADPH-binding sites." Haniu M., McManus M.E., Birkett D.J., Lee T.D., Shively J.E. Biochemistry 28:8639-8645(1989) [PubMed: 2513880] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-677. Tissue: Liver.
[7]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[8]	"Crystal structure of the FMN-binding domain of human cytochrome P450 reductase at 1.93 A resolution." Zhao Q., Modi S., Smith G., Paine M., McDonagh P.D., Wolf C.R., Tew D., Lian L.Y., Roberts G.C., Driessen H.P. Protein Sci. 8:298-306(1999) [PubMed: 10048323] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.93 ANGSTROMS) OF 62-242.
[9]	"Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome." Adachi M., Tachibana K., Asakura Y., Yamamoto T., Hanaki K., Oka A. Am. J. Med. Genet. A 128:333-339(2004) [PubMed: 15264278] [Abstract] Cited for: VARIANT AHV HIS-454.
[10]	"Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients." Fukami M., Horikawa R., Nagai T., Tanaka T., Naiki Y., Sato N., Okuyama T., Nakai H., Soneda S., Tachibana K., Matsuo N., Sato S., Homma K., Nishimura G., Hasegawa T., Ogata T. J. Clin. Endocrinol. Metab. 90:414-426(2005) [PubMed: 15483095] [Abstract] Cited for: VARIANTS AHV HIS-454; CYS-575 AND 608-LEU--TRP-617 DELINS ARG, VARIANT VAL-500.
[11]	"Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study." Arlt W., Walker E.A., Draper N., Ivison H.E., Ride J.P., Hammer F., Chalder S.M., Borucka-Mankiewicz M., Hauffa B.P., Malunowicz E.M., Stewart P.M., Shackleton C.H.L. Lancet 363:2128-2135(2004) [PubMed: 15220035] [Abstract] Cited for: VARIANTS AHV ASP-178; PRO-284; HIS-454 AND TYR-566, CHARACTERIZATION OF VARIANTS AHV ASP-178; PRO-284; HIS-454 AND TYR-566.
[12]	"Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome." Flueck C.E., Tajima T., Pandey A.V., Arlt W., Okuhara K., Verge C.F., Jabs E.W., Mendonca B.B., Fujieda K., Miller W.L. Nat. Genet. 36:228-230(2004) [PubMed: 14758361] [Abstract] Cited for: VARIANTS AHV PRO-284; HIS-454 AND GLU-489, VARIANTS IDS TYR-566 AND PHE-605, CHARACTERIZATION OF VARIANTS AHV PRO-284; HIS-454 AND GLU-489, CHARACTERIZATION OF VARIANTS IDS TYR-566 AND PHE-605.
+	Additional computationally mapped references.

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Web resources

GeneReviews

NIEHS-SNPs

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Cross-references

Sequence databases

S90469 mRNA. Translation: AAB21814.1.
AF258341 mRNA. Translation: AAG09798.1.
AB051763 mRNA. Translation: BAB18572.1.
DQ640499 Genomic DNA. Translation: ABF70199.1.
BC034277 mRNA. Translation: AAH34277.1. Different initiation.

IPI

IPI00470467.

PIR

A60557. A33421.

RefSeq

NP_000932.3.

UniGene

Hs.354056

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1B1C	X-ray	1.93	A	61-241	[»]

SMR

P16435. Positions 64-677.

ModBase

Search...

Protein-protein interaction databases

IntAct

P16435. 1 interaction.

PTM databases

PhosphoSite

P16435.

Proteomic databases

PRIDE

P16435.

Genome annotation databases

Ensembl

ENSG00000127948. Homo sapiens. [Contig view]

GeneID

5447.

KEGG

hsa:5447.

Organism-specific databases

GeneCards

GC07P075382.

H-InvDB

HIX0006782.

HGNC

HGNC:9208. POR.

HPA

CAB004372.
HPA010136.

MIM

124015. gene.
201750. phenotype.

Orphanet

83. Antley-Bixler syndrome.
63269. Antley-Bixler-like syndrome - ambiguous genitalia - disordered steroidogenesis.

PharmGKB

PA27834.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

P16435.

Enzyme and pathway databases

BRENDA

1.6.2.4. 247.

Gene expression databases

Bgee

P16435.

CleanEx

HS_POR.

GermOnline

ENSG00000127948. Homo sapiens.

Family and domain databases

InterPro

IPR003097. FAD-binding_1.
IPR017927. Fd_Rdtase_FAD-bd.
IPR001094. Flavdoxin-like.
IPR008254. Flavodoxin/NO_synth.
IPR001709. Flavoprot_Pyr_Nucl_cyt_Rdtase.
IPR015702. NADPH_Cyt_P450_Rdtase.
IPR001433. OxRdtase_FAD/NAD_bd.
[Graphical view]

PANTHER

PTHR19384:SF17. NADPH_Cyt_Red. 1 hit.

Pfam

PF00667. FAD_binding_1. 1 hit.
PF00258. Flavodoxin_1. 1 hit.
PF00175. NAD_binding_1. 1 hit.
[Graphical view]

PRINTS

PR00369. FLAVODOXIN.
PR00371. FPNCR.

PROSITE

PS51384. FAD_FR. 1 hit.
PS50902. FLAVODOXIN_LIKE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00865. Benzphetamine.
DB00694. Daunorubicin.
DB00166. Lipoic Acid.
DB00170. Menadione.
DB01028. Methoxyflurane.
DB00305. Mitomycin.
DB00665. Nilutamide.

NextBio

21083.

SOURCE

Search...

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Entry information

Entry name

NCPR_HUMAN

Accession

Primary (citable) accession number: P16435
Secondary accession number(s): Q16455

Q9H3M8

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1990
Last sequence update:	January 23, 2007
Last modified:	June 16, 2009
This is version 117 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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