Reviewed, UniProtKB/Swiss-Prot Q7L1T6 (NB5R4_HUMAN)

Names and origin

Protein names

Recommended name:
    Cytochrome b5 reductase 4
    EC=1.6.2.2
Alternative name(s):
    Flavohemoprotein b5/b5R
      Short name=b5+b5R
    cb5/cb5R
    N-terminal cytochrome b5 and cytochrome b5 oxidoreductase domain-containing protein

Gene names

Name:	CYB5R4
Synonyms:	NCB5OR

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	521 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	NADH-cytochrome b5 reductase involved in endolasmic reticulum stress response pathway. Plays a critical role in protecting pancreatic beta-cells against oxidant stress, possibly by protecting the cell from excess buildup of reactive oxygen species (ROS). Reduces a variety of substrates in vitro, such as cytochrome c, feericyanide and methemoglobin.
Catalytic activity	NADH + 2 ferricytochrome b5 = NAD+ + H+ + 2 ferrocytochrome b5.
Cofactor	FAD.
Subcellular location	Endoplasmic reticulum. Note: Soluble protein. Ref.4 Ref.6
Tissue specificity	Widely expressed. Ref.4
Polymorphism	Variants Arg-187 and Arg-223 do not influence the pathogenesis of non-autoimmune diabetes.
Sequence similarities	Belongs to the flavoprotein pyridine nucleotide cytochrome reductase family. Contains 1 CS domain. Contains 1 cytochrome b5 heme-binding domain. Contains 1 FAD-binding FR-type domain.
Biophysicochemical properties	Kinetic parameters: KM=25 mM for O2 Redox potential: E0 is -108 mV.
Sequence caution	The sequence CAI19905.1 differs from that shown. Reason: Erroneous gene model prediction. The sequence CAI22326.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum
Coding sequence diversity	Polymorphism
Ligand	FAD Flavoprotein Heme Iron Metal-binding NAD
Molecular function	Oxidoreductase
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	cell development Inferred from sequence or structural similarity. Source: UniProtKB detection of oxygen Ref.4 Non-traceable author statement. Source: UniProtKB generation of precursor metabolites and energy Ref.4 Inferred from direct assay. Source: UniProtKB glucose homeostasis Inferred from sequence or structural similarity. Source: UniProtKB insulin secretion Inferred from sequence or structural similarity. Source: UniProtKB oxidation reduction Ref.6 Inferred from direct assay. Source: UniProtKB response to antibiotic Inferred from sequence or structural similarity. Source: UniProtKB superoxide metabolic process Ref.4 Inferred from direct assay. Source: UniProtKB
Cellular component	endoplasmic reticulum Ref.6 Inferred from direct assay. Source: UniProtKB perinuclear region of cytoplasm Ref.4 Inferred from direct assay. Source: UniProtKB
Molecular function	NAD(P)H oxidase activity Ref.4 Ref.6 Inferred from direct assay. Source: UniProtKB cytochrome-b5 reductase activity Ref.4 Inferred from direct assay. Source: UniProtKB 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 – 521	521	Cytochrome b5 reductase 4		PRO_0000287556
Regions
	Domain	54 – 130	77	Cytochrome b5 heme-binding
	Domain	165 – 256	92	CS
	Domain	273 – 385	113	FAD-binding FR-type
	Nucleotide binding	365 – 380	16	FAD By similarity
	Nucleotide binding	392 – 424	33	FAD By similarity
Sites
	Metal binding	89	1	Iron (heme axial ligand) By similarity
	Metal binding	112	1	Iron (heme axial ligand) By similarity
Natural variations
	Natural variant	140	1	R → H		VAR_047967
	Natural variant	187	1	Q → R		VAR_032323
	Natural variant	223	1	H → R		VAR_032324
	Natural variant	267	1	P → A: dbSNP rs61382555. Ref.1		VAR_047968
	Natural variant	282	1	S → P: dbSNP rs10080628.		VAR_032325
	Natural variant	316	1	P → S: dbSNP rs10080628. Ref.1		VAR_047969
	Natural variant	371	1	D → Y in a breast cancer sample; somatic mutation. Ref.7		VAR_036240
	Natural variant	390	1	L → M in a breast cancer sample; somatic mutation. Ref.7		VAR_036241

Sequences

	Sequence		Length	Mass (Da)
	Q7L1T6-1 [UniParc]. Last modified August 30, 2005. Version 1. Checksum: 9D83BAB387E3B0F4	FASTA	521	59,474
	10 20 30 40 50 60 MLNVPSQSFP APRSQQRVAS GGRSKVPLKQ GRSLMDWIRL TKSGKDLTGL KGRLIEVTEE 70 80 90 100 110 120 ELKKHNKKDD CWICIRGFVY NVSPYMEYHP GGEDELMRAA GSDGTELFDQ VHRWVNYESM 130 140 150 160 170 180 LKECLVGRMA IKPAVLKDYR EEEKKVLNGM LPKSQVTDTL AKEGPSYPSY DWFQTDSLVT 190 200 210 220 230 240 IAIYTKQKDI NLDSIIVDHQ NDSFRAETII KDCLYLIHIG LSHEVQEDFS VRVVESVGKI 250 260 270 280 290 300 EIVLQKKENT SWDFLGHPLK NHNSLIPRKD TGLYYRKCQL ISKEDVTHDT RLFCLMLPPS 310 320 330 340 350 360 THLQVPIGQH VYLKLPITGT EIVKPYTPVS GSLLSEFKEP VLPNNKYIYF LIKIYPTGLF 370 380 390 400 410 420 TPELDRLQIG DFVSVSSPEG NFKISKFQEL EDLFLLAAGT GFTPMVKILN YALTDIPSLR 430 440 450 460 470 480 KVKLMFFNKT EDDIIWRSQL EKLAFKDKRL DVEFVLSAPI SEWNGKQGHI SPALLSEFLK 490 500 510 520 RNLDKSKVLV CICGPVPFTE QGVRLLHDLN FSKNEIHSFT A

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	SeattleSNPs variation discovery resource Submitted (FEB-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HIS-140; ALA-267 AND SER-316.
[2]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed: 14574404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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: Testis.
[4]	"Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously expressed in human cells." Zhu H., Qiu H., Yoon H.-W., Huang S., Bunn H.F. Proc. Natl. Acad. Sci. U.S.A. 96:14742-14747(1999) [PubMed: 10611283] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 33-521, SUBCELLULAR LOCATION, HEME-BINDING, FAD-BINDING, TISSUE SPECIFICITY.
[5]	"Variation in NCB5OR: studies of relationships to type 2 diabetes, maturity-onset diabetes of the young, and gestational diabetes mellitus." Andersen G., Wegner L., Rose C.S., Xie J., Zhu H., Larade K., Johansen A., Ek J., Lauenborg J., Drivsholm T., Borch-Johnsen K., Damm P., Hansen T., Bunn H.F., Pedersen O. Diabetes 53:2992-2997(2004) [PubMed: 15504981] [Abstract] Cited for: VARIANTS ARG-187 AND ARG-223.
[6]	"NCB5OR is a novel soluble NAD(P)H reductase localized in the endoplasmic reticulum." Zhu H., Larade K., Jackson T.A., Xie J., Ladoux A., Acker H., Berchner-Pfannschmidt U., Fandrey J., Cross A.R., Lukat-Rodgers G.S., Rodgers K.R., Bunn H.F. J. Biol. Chem. 279:30316-30325(2004) [PubMed: 15131110] [Abstract] Cited for: SUBCELLULAR LOCATION.
[7]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] TYR-371 AND MET-390.

Web resources

SeattleSNPs

Cross-references

Sequence databases
EMBL GenBank DDBJ	EU448291 Genomic DNA. Translation: ACA06109.1. AL139232, AL034347 Genomic DNA. Translation: CAI19904.2. AL034347, AL139232 Genomic DNA. Translation: CAI22325.2. AL034347, AL139232 Genomic DNA. Translation: CAI22326.1. Sequence problems. AL139232, AL034347 Genomic DNA. Translation: CAI19905.1. Sequence problems. BC025380 mRNA. Translation: AAH25380.2. AF169803 mRNA. Translation: AAF04812.1. Different initiation.
IPI	IPI00008236.
RefSeq	NP_057314.2.
UniGene	Hs.5741
3D structure databases
HSSP	HSSP built from PDB template 1SH4 based on UniProtKB P00171.
SMR	Q7L1T6. Positions 54-129, 163-259, 262-519.
ModBase	Search...
Protein-protein interaction databases
STRING	Q7L1T6.
Proteomic databases
PRIDE	Q7L1T6.
Genome annotation databases
Ensembl	ENST00000369681; ENSP00000358695; ENSG00000065615; Homo sapiens. [Genome view]
GeneID	51167.
KEGG	hsa:51167.
NMPDR	fig|9606.3.peg.27467.
UCSC	uc003pkf.1. human.
Organism-specific databases
CTD	51167.
GeneCards	GC06P084627.
HGNC	HGNC:20147. CYB5R4.
HPA	HPA018992.
MIM	608343. gene.
PharmGKB	PA134904907.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG12233.
HOGENOM	HBG717192.
HOVERGEN	Q7L1T6.
InParanoid	Q7L1T6.
OMA	LIKIYPA.
OrthoDB	EOG9T7BPH.
PhylomeDB	Q7L1T6.
Enzyme and pathway databases
BRENDA	1.6.2.2. 247.
Gene expression databases
ArrayExpress	Q7L1T6.
Bgee	Q7L1T6.
CleanEx	HS_CYB5R4.
Genevestigator	Q7L1T6.
Family and domain databases
InterPro	IPR017447. CS. IPR007052. CS_domain. IPR001199. Cyt_B5. IPR018506. Cyt_B5_heme-BS. IPR017927. Fd_Rdtase_FAD-bd. IPR008978. HSP20-like_chaperone. IPR001834. NADH-Cyt_B5_reductase. IPR008333. OxRdtase_FAD-bd_dom. IPR001433. OxRdtase_FAD/NAD_bd. IPR017938. Riboflavin_synthase-like_b-brl. [Graphical view]
Gene3D	G3DSA:3.10.120.10. Cyt_B5. 1 hit.
Pfam	PF04969. CS. 1 hit. PF00173. Cyt-b5. 1 hit. PF00970. FAD_binding_6. 1 hit. PF00175. NAD_binding_1. 1 hit. [Graphical view]
PRINTS	PR00406. CYTB5RDTASE. PR00363. CYTOCHROMEB5.
PROSITE	PS51203. CS. 1 hit. PS00191. CYTOCHROME_B5_1. 1 hit. PS50255. CYTOCHROME_B5_2. 1 hit. PS51384. FAD_FR. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	54103.
SOURCE	Search...

Entry information

Entry name

NB5R4_HUMAN

Accession

Primary (citable) accession number: Q7L1T6
Secondary accession number(s): B1AEM2 , Q5TGI9, Q9NUE4, Q9UHI9

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 15, 2007
Last sequence update:	August 30, 2005
Last modified:	January 19, 2010
This is version 51 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.