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    CYB5R3 cytochrome b5 reductase 3 [ Homo sapiens (human) ]

    Gene ID: 1727, updated on 3-Nov-2024

    Summary

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    Official Symbol
    CYB5R3provided by HGNC
    Official Full Name
    cytochrome b5 reductase 3provided by HGNC
    Primary source
    HGNC:HGNC:2873
    See related
    Ensembl:ENSG00000100243 MIM:613213; AllianceGenome:HGNC:2873
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    B5R; DIA1
    Summary
    This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]
    Expression
    Ubiquitous expression in fat (RPKM 110.9), testis (RPKM 52.5) and 24 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See CYB5R3 in Genome Data Viewer
    Location:
    22q13.2
    Exon count:
    12
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 22 NC_000022.11 (42617840..42649392, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 22 NC_060946.1 (43098710..43130267, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 22 NC_000022.10 (43013846..43045398, complement)

    Chromosome 22 - NC_000022.11Genomic Context describing neighboring genes Neighboring gene DNA polymerase delta interacting protein 3 Neighboring gene uncharacterized LOC124905127 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43009109-43009652 Neighboring gene H3K27ac hESC enhancer GRCh37_chr22:43010197-43010740 Neighboring gene H3K27ac hESC enhancer GRCh37_chr22:43010741-43011284 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19174 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19175 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43019599-43020153 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43027517-43028018 Neighboring gene RNA, U12 small nuclear Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43032221-43032758 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43032759-43033294 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43040225-43041216 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13834 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13835 Neighboring gene H3K27ac hESC enhancer GRCh37_chr22:43045573-43046386 Neighboring gene ATP synthase membrane subunit g like Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13837 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13838 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13839 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43082077-43082968 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43082969-43083858 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43083859-43084750 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43089063-43089584 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43089979-43090480 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43090481-43090980 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43094281-43094964 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43094965-43095648 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43097017-43097700 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43098815-43099314 Neighboring gene ReSE screen-validated silencer GRCh37_chr22:43103268-43103479 Neighboring gene alpha 1,4-galactosyltransferase (P1PK blood group) Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19176 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13840 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13841 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 13842 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr22:43136606-43137182 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43138337-43138912 Neighboring gene Sharpr-MPRA regulatory region 8887 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr22:43139489-43140064 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr22:43144579-43145140 Neighboring gene Sharpr-MPRA regulatory region 987 Neighboring gene ReSE screen-validated silencer GRCh37_chr22:43165586-43165772 Neighboring gene ribosomal protein L5 pseudogene 34

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    Related articles in PubMed

    1. Prenatal diagnosis of recessive congenital methaemoglobinaemia type II: novel mutation in the NADH-cytochrome b5 reductase gene leading to stop codon read-through. Leroux A, et al. Eur J Haematol, 2005 May. PMID 15813912
    2. Identification of alternative first exons of NADH-cytochrome b5 reductase gene expressed ubiquitously in human cells. Du M, et al. Biochem Biophys Res Commun, 1997 Jun 27. PMID 9207238
    3. Recessive congenital methaemoglobinaemia type II a new mutation which causes incorrect splicing in the NADH-cytochrome b5 reductase gene. Owen EP, et al. J Inherit Metab Dis, 1997 Aug. PMID 9266404
    4. An erythroid-specific transcript generates the soluble form of NADH-cytochrome b5 reductase in humans. Bulbarelli A, et al. Blood, 1998 Jul 1. PMID 9639531
    5. Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia. Deorukhkar A, et al. Mol Biol Rep, 2022 Mar. PMID 35064402

    See all (171) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults.
      Title: CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults.
    2. Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia.
      Title: Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia.
    3. Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia.
      Title: Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia.
    4. The CYB5R3(c) (.350C>G) and G6PD A alleles modify severity of anemia in malaria and sickle cell disease.
      Title: The CYB5R3(c) (.350C>G) and G6PD A alleles modify severity of anemia in malaria and sickle cell disease.
    5. study indicated that novel homozygous mutation p.Arg192Cys in CYB5R3 gene present in eight cases and the possibility of high prevalence of heterozygous in Indian population causing Type I recessive congenital methemoglobinemia.
      Title: Novel mutation (R192C) in CYB5R3 gene causing NADH-cytochrome b5 reductase deficiency in eight Indian patients associated with autosomal recessive congenital methemoglobinemia type-I.
    6. Data suggest that cytochrome b5 (CYB5) and cytochrome b5 reductase 3 (CYB5R3) can reduce human cytoglobin (CYGB) and zebrafish cytoglobins at rates up to 250-fold higher than those reported for the known physiological substrates, hemoglobin and myoglobin; the three proteins (CYB5+CYB5R3+CYGB) appear to constitute a metabolon involved in generation of nitric oxide.
      Title: Efficient Reduction of Vertebrate Cytoglobins by the Cytochrome b(5)/Cytochrome b(5) Reductase/NADH System.
    7. CYB5R3 promotes colonization and metastasis formation and is a prognostic marker of disease-free and overall survival in estrogen receptor-negative breast cancer.
      Title: NADH-Cytochrome b5 Reductase 3 Promotes Colonization and Metastasis Formation and Is a Prognostic Marker of Disease-Free and Overall Survival in Estrogen Receptor-Negative Breast Cancer.
    8. Variants in CYB5A and CYB5R3 should be considered in the evaluation of breast cancer risk in African American women.
      Title: Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women.
    9. Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy.
      Title: Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy.
    10. The results unveil a potential mechanism of action by which CYB5R3 deficiency contributes to the pathophysiological underpinnings of neurological disorders in RHM patients.
      Title: Membrane-bound CYB5R3 is a common effector of nutritional and oxidative stress response through FOXO3a and Nrf2.
    Submit: New GeneRIF Correction See all GeneRIFs (31)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Deficiency of cytochrome-b5 reductase
    MedGen: C0268193 OMIM: 250800 GeneReviews: Not available
    		Compare labs

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    HIV-1 interactions

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    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp160, precursor env HIV-1 gp160 interacts with CYB5R PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ADP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables AMP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables FAD binding IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables FAD binding IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables NAD binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables cytochrome-b5 reductase activity, acting on NAD(P)H IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables cytochrome-b5 reductase activity, acting on NAD(P)H IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    contributes_to nitrite reductase (NO-forming) activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in blood circulation TAS
    Traceable Author Statement
    more info
    		 PubMed 
    involved_in cholesterol biosynthetic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in nitric oxide biosynthetic process IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in azurophil granule lumen TAS
    Traceable Author Statement
    more info
    		  
    located_in cytoplasm TAS
    Traceable Author Statement
    more info
    		 PubMed 
    located_in cytosol IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in endoplasmic reticulum IDA
    Inferred from Direct Assay
    more info
    		  
    is_active_in endoplasmic reticulum membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in endoplasmic reticulum membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in extracellular region TAS
    Traceable Author Statement
    more info
    		  
    part_of hemoglobin complex TAS
    Traceable Author Statement
    more info
    		 PubMed 
    located_in lipid droplet IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in membrane HDA PubMed 
    located_in mitochondrial membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in mitochondrial outer membrane TAS
    Traceable Author Statement
    more info
    		  
    located_in mitochondrion HDA PubMed 
    located_in mitochondrion HTP PubMed 
    is_active_in mitochondrion IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    part_of nitric-oxide synthase complex IDA
    Inferred from Direct Assay
    more info
    		 PubMed 

    General protein information

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    Preferred Names
    NADH-cytochrome b5 reductase 3
    Names
    NADH-cytochrome b5 reductase 3 membrane-bound form
    NADH-cytochrome b5 reductase 3 soluble form
    diaphorase-1
    mutant NADH-cytochrome b5 reductase
    NP_000389.1
    NP_001123291.1
    NP_001165131.1
    NP_001165132.1
    NP_015565.1
    XP_047297139.1
    XP_054181199.1

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_012194.1 RefSeqGene

      Range
      5008..36560
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_000398.7 → NP_000389.1  NADH-cytochrome b5 reductase 3 isoform 1

      See identical proteins and their annotated locations for NP_000389.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the membrane-bound form (isoform 1) of the enzyme. This isoform (1) is referred to in the literature as isoform m.
      Source sequence(s)
      BC004821, BX334220, Z93241
      Consensus CDS
      CCDS33658.1
      UniProtKB/Swiss-Prot
      B1AHF2, B7Z7L3, O75675, P00387, Q8TDL8, Q8WTS8, Q9UEN4, Q9UEN5, Q9UL55, Q9UL56
      UniProtKB/TrEMBL
      A0A8J8Z3C6
      Related
      ENSP00000338461.6, ENST00000352397.10
      Conserved Domains (2) summary
      cd06183
      Location:45 → 301
      cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
      PTZ00319
      Location:11 → 301
      PTZ00319; NADH-cytochrome B5 reductase; Provisional

    2. NM_001129819.2 → NP_001123291.1  NADH-cytochrome b5 reductase 3 isoform 2

      See identical proteins and their annotated locations for NP_001123291.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) has an alternate 5' exon, as compared to variant 1. The resulting isoform (2) is the soluble form of the enzyme, which has a shorter N-terminus when it is compared to the membrane-bound form. This isoform (2) is referred to in the literature as isoform s.
      Source sequence(s)
      AJ310900, DA268749, DA548643, Z93241
      Consensus CDS
      CCDS14040.1
      UniProtKB/TrEMBL
      A0A8J8Z3C6
      Related
      ENSP00000384834.3, ENST00000407623.8
      Conserved Domains (2) summary
      cd06183
      Location:22 → 278
      cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
      PTZ00319
      Location:3 → 278
      PTZ00319; NADH-cytochrome B5 reductase; Provisional

    3. NM_001171660.2 → NP_001165131.1  NADH-cytochrome b5 reductase 3 isoform 3

      See identical proteins and their annotated locations for NP_001165131.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) differs in the 5' UTR and 5' coding region and initiates translation at an alternate start codon, compared to variant 1. The encoded isoform (3) is longer and has a distinct N-terminus, compared to isoform 1.
      Source sequence(s)
      AK302204, Z93241
      Consensus CDS
      CCDS54535.1
      UniProtKB/TrEMBL
      A0A8J8Z3C6
      Related
      ENSP00000509015.1, ENST00000688117.1
      Conserved Domains (2) summary
      cd06183
      Location:78 → 334
      cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
      PTZ00319
      Location:44 → 334
      PTZ00319; NADH-cytochrome B5 reductase; Provisional

    4. NM_001171661.1 → NP_001165132.1  NADH-cytochrome b5 reductase 3 isoform 2

      See identical proteins and their annotated locations for NP_001165132.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) uses an alternate exon in the 5' UTR and 5' coding region, compared to variant 1. The resulting isoform (2) is the soluble form of the enzyme, which has a shorter N-terminus when it is compared to the membrane-bound form. This isoform (2) is referred to in the literature as isoform s.
      Source sequence(s)
      BM564146, Z93241
      Consensus CDS
      CCDS14040.1
      UniProtKB/TrEMBL
      A0A8J8Z3C6
      Related
      ENSP00000385679.1, ENST00000402438.6
      Conserved Domains (2) summary
      cd06183
      Location:22 → 278
      cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
      PTZ00319
      Location:3 → 278
      PTZ00319; NADH-cytochrome B5 reductase; Provisional

    5. NM_007326.4 → NP_015565.1  NADH-cytochrome b5 reductase 3 isoform 2

      See identical proteins and their annotated locations for NP_015565.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) uses an alternate exon in the 5' UTR and 5' coding region, compared to variant 1. The resulting isoform (2) is the soluble form of the enzyme, which has a shorter N-terminus when it is compared to the membrane-bound form. This isoform (2) is referred to in the literature as isoform s.
      Source sequence(s)
      AJ310900, DB029897, Z93241
      Consensus CDS
      CCDS14040.1
      UniProtKB/TrEMBL
      A0A8J8Z3C6
      Related
      ENSP00000508492.1, ENST00000687198.1
      Conserved Domains (2) summary
      cd06183
      Location:22 → 278
      cyt_b5_reduct_like; Cytochrome b5 reductase catalyzes the reduction of 2 molecules of cytochrome b5 using NADH as an electron donor. Like ferredoxin reductases, these proteins have an N-terminal FAD binding subdomain and a C-terminal NADH binding subdomain, separated by a ...
      PTZ00319
      Location:3 → 278
      PTZ00319; NADH-cytochrome B5 reductase; Provisional

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000022.11 Reference GRCh38.p14 Primary Assembly

      Range
      42617840..42649392 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047441183.1 → XP_047297139.1  NADH-cytochrome b5 reductase 3 isoform X1

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060946.1 Alternate T2T-CHM13v2.0

      Range
      43098710..43130267 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054325224.1 → XP_054181199.1  NADH-cytochrome b5 reductase 3 isoform X1

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    P00387.3 GenPept UniProtKB/Swiss-Prot:P00387

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