ID   NB5R2_HUMAN             Reviewed;         276 AA.
AC   Q6BCY4; Q9BVA3; Q9UF68; Q9UHJ0;
DT   15-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT   13-SEP-2004, sequence version 1.
DT   27-MAR-2024, entry version 150.
DE   RecName: Full=NADH-cytochrome b5 reductase 2 {ECO:0000305};
DE            Short=b5R.2;
DE            EC=1.6.2.2 {ECO:0000305|PubMed:15858218};
GN   Name=CYB5R2 {ECO:0000312|HGNC:HGNC:24376};
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] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP   ASP-209.
RX   PubMed=10611283; DOI=10.1073/pnas.96.26.14742;
RA   Zhu H., Qiu H., Yoon H.-W., Huang S., Bunn H.F.;
RT   "Identification of a cytochrome b-type NAD(P)H oxidoreductase ubiquitously
RT   expressed in human cells.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:14742-14747(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY.
RX   PubMed=15858218; DOI=10.1095/biolreprod.104.037960;
RA   Baker M.A., Krutskikh A., Curry B.J., Hetherington L., Aitken R.J.;
RT   "Identification of cytochrome-b5 reductase as the enzyme responsible for
RT   NADH-dependent lucigenin chemiluminescence in human spermatozoa.";
RL   Biol. Reprod. 73:334-342(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ASP-209.
RC   TISSUE=Placenta;
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 [LARGE SCALE MRNA] OF 7-276 (ISOFORM 1), AND VARIANT
RP   ASP-209.
RC   TISSUE=Testis;
RX   PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA   Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA   Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA   Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA   Wiemann S., Schupp I.;
RT   "The full-ORF clone resource of the German cDNA consortium.";
RL   BMC Genomics 8:399-399(2007).
CC   -!- FUNCTION: NADH-cytochrome b5 reductases are involved in desaturation
CC       and elongation of fatty acids, cholesterol biosynthesis, drug
CC       metabolism, and, in erythrocyte, methemoglobin reduction (By
CC       similarity). Responsible for NADH-dependent lucigenin chemiluminescence
CC       in spermatozoa by reducing both lucigenin and 2-[4-iodophenyl]-3-[4-
CC       nitrophenyl]-5-[2,4-disulfophenyl]-2H tetrazolium monosodium salt (WST-
CC       1). {ECO:0000250, ECO:0000269|PubMed:15858218}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=2 Fe(III)-[cytochrome b5] + NADH = 2 Fe(II)-[cytochrome b5] +
CC         H(+) + NAD(+); Xref=Rhea:RHEA:46680, Rhea:RHEA-COMP:10438, Rhea:RHEA-
CC         COMP:10439, ChEBI:CHEBI:15378, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.6.2.2;
CC         Evidence={ECO:0000305|PubMed:15858218};
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000250};
CC   -!- INTERACTION:
CC       Q6BCY4; Q9UJX2: CDC23; NbExp=3; IntAct=EBI-744761, EBI-396137;
CC       Q6BCY4; Q08379: GOLGA2; NbExp=3; IntAct=EBI-744761, EBI-618309;
CC       Q6BCY4; P62333: PSMC6; NbExp=3; IntAct=EBI-744761, EBI-357669;
CC       Q6BCY4; Q13077: TRAF1; NbExp=3; IntAct=EBI-744761, EBI-359224;
CC       Q6BCY4; Q12933: TRAF2; NbExp=3; IntAct=EBI-744761, EBI-355744;
CC       Q6BCY4; Q15645: TRIP13; NbExp=4; IntAct=EBI-744761, EBI-358993;
CC       Q6BCY4-2; O95994: AGR2; NbExp=3; IntAct=EBI-12102608, EBI-712648;
CC       Q6BCY4-2; Q9NW38: FANCL; NbExp=3; IntAct=EBI-12102608, EBI-2339898;
CC       Q6BCY4-2; Q08379: GOLGA2; NbExp=3; IntAct=EBI-12102608, EBI-618309;
CC       Q6BCY4-2; O14964: HGS; NbExp=3; IntAct=EBI-12102608, EBI-740220;
CC       Q6BCY4-2; Q9H944: MED20; NbExp=3; IntAct=EBI-12102608, EBI-394644;
CC       Q6BCY4-2; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-12102608, EBI-16439278;
CC       Q6BCY4-2; Q8NI38: NFKBID; NbExp=3; IntAct=EBI-12102608, EBI-10271199;
CC       Q6BCY4-2; Q04864-2: REL; NbExp=3; IntAct=EBI-12102608, EBI-10829018;
CC       Q6BCY4-2; P51687: SUOX; NbExp=3; IntAct=EBI-12102608, EBI-3921347;
CC       Q6BCY4-2; Q12933: TRAF2; NbExp=3; IntAct=EBI-12102608, EBI-355744;
CC       Q6BCY4-2; Q15645: TRIP13; NbExp=3; IntAct=EBI-12102608, EBI-358993;
CC       Q6BCY4-2; Q96MU6-2: ZNF778; NbExp=3; IntAct=EBI-12102608, EBI-14242669;
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q6BCY4-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q6BCY4-2; Sequence=VSP_025559;
CC   -!- TISSUE SPECIFICITY: Restricted expression.
CC       {ECO:0000269|PubMed:10611283}.
CC   -!- SIMILARITY: Belongs to the flavoprotein pyridine nucleotide cytochrome
CC       reductase family. {ECO:0000305}.
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; AF169802; AAF04811.1; -; mRNA.
DR   EMBL; AY665398; AAT75296.1; -; mRNA.
DR   EMBL; BC001346; AAH01346.1; -; mRNA.
DR   EMBL; AL133582; CAB63726.1; -; mRNA.
DR   CCDS; CCDS7780.1; -. [Q6BCY4-1]
DR   PIR; T43491; T43491.
DR   RefSeq; NP_001289755.1; NM_001302826.1. [Q6BCY4-1]
DR   RefSeq; NP_057313.2; NM_016229.4. [Q6BCY4-1]
DR   RefSeq; XP_005253032.1; XM_005252975.4.
DR   RefSeq; XP_006718314.1; XM_006718251.2. [Q6BCY4-1]
DR   RefSeq; XP_011518486.1; XM_011520184.2. [Q6BCY4-1]
DR   AlphaFoldDB; Q6BCY4; -.
DR   SMR; Q6BCY4; -.
DR   BioGRID; 119684; 32.
DR   IntAct; Q6BCY4; 18.
DR   STRING; 9606.ENSP00000437041; -.
DR   iPTMnet; Q6BCY4; -.
DR   PhosphoSitePlus; Q6BCY4; -.
DR   BioMuta; CYB5R2; -.
DR   DMDM; 74709211; -.
DR   REPRODUCTION-2DPAGE; IPI00332396; -.
DR   EPD; Q6BCY4; -.
DR   jPOST; Q6BCY4; -.
DR   MassIVE; Q6BCY4; -.
DR   MaxQB; Q6BCY4; -.
DR   PaxDb; 9606-ENSP00000437041; -.
DR   PeptideAtlas; Q6BCY4; -.
DR   ProteomicsDB; 66216; -. [Q6BCY4-1]
DR   ProteomicsDB; 66217; -. [Q6BCY4-2]
DR   Pumba; Q6BCY4; -.
DR   Antibodypedia; 24030; 158 antibodies from 23 providers.
DR   DNASU; 51700; -.
DR   Ensembl; ENST00000299498.11; ENSP00000299498.6; ENSG00000166394.15. [Q6BCY4-1]
DR   Ensembl; ENST00000524790.5; ENSP00000435916.1; ENSG00000166394.15. [Q6BCY4-2]
DR   Ensembl; ENST00000533558.5; ENSP00000437041.1; ENSG00000166394.15. [Q6BCY4-1]
DR   GeneID; 51700; -.
DR   KEGG; hsa:51700; -.
DR   MANE-Select; ENST00000299498.11; ENSP00000299498.6; NM_016229.5; NP_057313.2.
DR   UCSC; uc001mfm.4; human. [Q6BCY4-1]
DR   AGR; HGNC:24376; -.
DR   CTD; 51700; -.
DR   DisGeNET; 51700; -.
DR   GeneCards; CYB5R2; -.
DR   HGNC; HGNC:24376; CYB5R2.
DR   HPA; ENSG00000166394; Tissue enhanced (retina, testis).
DR   MIM; 608342; gene.
DR   neXtProt; NX_Q6BCY4; -.
DR   OpenTargets; ENSG00000166394; -.
DR   PharmGKB; PA142672060; -.
DR   VEuPathDB; HostDB:ENSG00000166394; -.
DR   eggNOG; KOG0534; Eukaryota.
DR   GeneTree; ENSGT00940000153962; -.
DR   HOGENOM; CLU_003827_9_2_1; -.
DR   InParanoid; Q6BCY4; -.
DR   OMA; EVEAMMY; -.
DR   OrthoDB; 979728at2759; -.
DR   PhylomeDB; Q6BCY4; -.
DR   TreeFam; TF314333; -.
DR   BRENDA; 1.6.2.2; 2681.
DR   PathwayCommons; Q6BCY4; -.
DR   Reactome; R-HSA-1237044; Erythrocytes take up carbon dioxide and release oxygen.
DR   SignaLink; Q6BCY4; -.
DR   BioGRID-ORCS; 51700; 11 hits in 1159 CRISPR screens.
DR   GeneWiki; CYB5R2; -.
DR   GenomeRNAi; 51700; -.
DR   Pharos; Q6BCY4; Tbio.
DR   PRO; PR:Q6BCY4; -.
DR   Proteomes; UP000005640; Chromosome 11.
DR   RNAct; Q6BCY4; Protein.
DR   Bgee; ENSG00000166394; Expressed in left testis and 169 other cell types or tissues.
DR   ExpressionAtlas; Q6BCY4; baseline and differential.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR   GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR   GO; GO:0005634; C:nucleus; HDA:UniProtKB.
DR   GO; GO:0004128; F:cytochrome-b5 reductase activity, acting on NAD(P)H; IDA:UniProtKB.
DR   GO; GO:0071949; F:FAD binding; IBA:GO_Central.
DR   GO; GO:0015701; P:bicarbonate transport; TAS:Reactome.
DR   GO; GO:0016126; P:sterol biosynthetic process; IEA:UniProtKB-KW.
DR   CDD; cd06183; cyt_b5_reduct_like; 1.
DR   Gene3D; 3.40.50.80; Nucleotide-binding domain of ferredoxin-NADP reductase (FNR) module; 1.
DR   Gene3D; 2.40.30.10; Translation factors; 1.
DR   InterPro; IPR001834; CBR-like.
DR   InterPro; IPR008333; Cbr1-like_FAD-bd_dom.
DR   InterPro; IPR017927; FAD-bd_FR_type.
DR   InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase.
DR   InterPro; IPR039261; FNR_nucleotide-bd.
DR   InterPro; IPR001433; OxRdtase_FAD/NAD-bd.
DR   InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR   PANTHER; PTHR19370; NADH-CYTOCHROME B5 REDUCTASE; 1.
DR   PANTHER; PTHR19370:SF185; NADH-CYTOCHROME B5 REDUCTASE 2; 1.
DR   Pfam; PF00970; FAD_binding_6; 1.
DR   Pfam; PF00175; NAD_binding_1; 1.
DR   PRINTS; PR00406; CYTB5RDTASE.
DR   PRINTS; PR00371; FPNCR.
DR   SUPFAM; SSF52343; Ferredoxin reductase-like, C-terminal NADP-linked domain; 1.
DR   SUPFAM; SSF63380; Riboflavin synthase domain-like; 1.
DR   PROSITE; PS51384; FAD_FR; 1.
DR   Genevisible; Q6BCY4; HS.
PE   1: Evidence at protein level;
KW   Acetylation; Alternative splicing; FAD; Flavoprotein; Lipid biosynthesis;
KW   Lipid metabolism; NAD; Oxidoreductase; Phosphoprotein; Reference proteome;
KW   Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW   Sterol metabolism.
FT   CHAIN           1..276
FT                   /note="NADH-cytochrome b5 reductase 2"
FT                   /id="PRO_0000287548"
FT   DOMAIN          15..127
FT                   /note="FAD-binding FR-type"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00716"
FT   BINDING         107..137
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         146..181
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         17
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:P00387"
FT   MOD_RES         18
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:P00387"
FT   VAR_SEQ         221..276
FT                   /note="WKYSSGFVTADMIKEHLPPPAKSTLILVCGPPPLIQTAAHPNLEKLGYTQDM
FT                   IFTY -> PWSAEGATLLSNSAQFH (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_025559"
FT   VARIANT         15
FT                   /note="E -> A (in dbSNP:rs11041525)"
FT                   /id="VAR_032321"
FT   VARIANT         209
FT                   /note="N -> D (in dbSNP:rs12801394)"
FT                   /evidence="ECO:0000269|PubMed:10611283,
FT                   ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17974005"
FT                   /id="VAR_032322"
FT   CONFLICT        130
FT                   /note="G -> R (in Ref. 1; AAF04811)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        253
FT                   /note="P -> T (in Ref. 1; AAF04811)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   276 AA;  31458 MW;  A475039D1E56ABDA CRC64;
     MNSRRREPIT LQDPEAKYPL PLIEKEKISH NTRRFRFGLP SPDHVLGLPV GNYVQLLAKI
     DNELVVRAYT PVSSDDDRGF VDLIIKIYFK NVHPQYPEGG KMTQYLENMK IGETIFFRGP
     RGRLFYHGPG NLGIRPDQTS EPKKTLADHL GMIAGGTGIT PMLQLIRHIT KDPSDRTRMS
     LIFANQTEED ILVRKELEEI ARTHPDQFNL WYTLDRPPIG WKYSSGFVTA DMIKEHLPPP
     AKSTLILVCG PPPLIQTAAH PNLEKLGYTQ DMIFTY
//