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    PFKFB4 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 [ Homo sapiens (human) ]

    Gene ID: 5210, updated on 3-Apr-2024

    Summary

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    Official Symbol
    PFKFB4provided by HGNC
    Official Full Name
    6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4provided by HGNC
    Primary source
    HGNC:HGNC:8875
    See related
    Ensembl:ENSG00000114268 MIM:605320; AllianceGenome:HGNC:8875
    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
    Summary
    The protein encoded by this gene is one of four bifunctional kinase/phosphatases that regulate the concentration of the glycolytic byproduct fructose-2,6-bisphosphate (F2,6BP). The encoded protein is highly expressed in cancer cells and is induced by hypoxia. This protein is essential to the survival of cancer cells under conditions of hypoxia, because it increases the amount of F2,6BP and ATP at a time when the cell cannot produce much of them. This finding suggests that this protein may be a good target for disruption in cancer cells, hopefully imperiling their survival. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]
    Expression
    Broad expression in testis (RPKM 10.5), small intestine (RPKM 8.0) and 18 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See PFKFB4 in Genome Data Viewer
    Location:
    3p21.31
    Exon count:
    21
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (48517684..48563136, complement)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (48546648..48592093, complement)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (48555117..48598562, complement)

    Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene ATRIP-TREX1 readthrough Neighboring gene ATR interacting protein Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48507557-48508438 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48508439-48509318 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48509460-48510226 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19831 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48513959-48514818 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19833 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48515680-48516539 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19834 Neighboring gene three prime repair exonuclease 1 Neighboring gene shisa family member 5 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14332 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14333 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48542139-48542692 Neighboring gene MPRA-validated peak4641 silencer Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:48587865-48588528 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:48588529-48589190 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48589191-48589854 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48589855-48590516 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19835 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19836 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48596699-48597640 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19837 Neighboring gene microRNA 6823 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48605535-48606482 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48607079-48607628 Neighboring gene collagen type VII alpha 1 chain Neighboring gene urocortin 2 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48625763-48626466 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48626467-48627168 Neighboring gene microRNA 711 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48638465-48638965 Neighboring gene ubiquinol-cytochrome c reductase core protein 1 Neighboring gene small nucleolar RNA, H/ACA box 94

    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
    • 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. PFKFB4 Is a Metabolic Driver of HCC Progression and Chemoresistance Through ROS Mitigation. Olaizola P, et al. Cell Mol Gastroenterol Hepatol, 2023. PMID 36963434, Free PMC Article
    2. PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner. Kam CS, et al. Cell Mol Gastroenterol Hepatol, 2023. PMID 36806581, Free PMC Article
    3. Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells. Wu Y, et al. J Obstet Gynaecol, 2022 Aug. PMID 35659173
    4. PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance. Feng C, et al. J Exp Clin Cancer Res, 2021 Sep 30. PMID 34593007, Free PMC Article
    5. Expression of Alternative Splice Variants of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase-4 in Normoxic and Hypoxic Melanoma Cells. Trojan SE, et al. Int J Mol Sci, 2021 Aug 17. PMID 34445551, Free PMC Article

    See all (67) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Transforming growth factor beta1 upregulates 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-4 expression in A549 and MCF-10A cells.
      Title: Transforming growth factor β1 upregulates 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-4 expression in A549 and MCF-10A cells.
    2. THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification.
      Title: THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification.
    3. PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner.
      Title: PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner.
    4. PFKFB4 Is a Metabolic Driver of HCC Progression and Chemoresistance Through ROS Mitigation.
      Title: PFKFB4 Is a Metabolic Driver of HCC Progression and Chemoresistance Through ROS Mitigation.
    5. Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells.
      Title: Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells.
    6. Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis.
      Title: Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis.
    7. PFKFB4 modulated by miR-195-5p can boost the malignant progression of cervical cancer cells.
      Title: PFKFB4 modulated by miR-195-5p can boost the malignant progression of cervical cancer cells.
    8. PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma.
      Title: PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma.
    9. Hypoxia-inducible CircPFKFB4 Promotes Breast Cancer Progression by Facilitating the CRL4(DDB2) E3 Ubiquitin Ligase-mediated p27 Degradation.
      Title: Hypoxia-inducible CircPFKFB4 Promotes Breast Cancer Progression by Facilitating the CRL4(DDB2) E3 Ubiquitin Ligase-mediated p27 Degradation.
    10. PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance.
      Title: PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance.
    Submit: New GeneRIF Correction See all GeneRIFs (40)

    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

    EBI GWAS Catalog

    Description
    A genome-wide association study identifies a novel locus at 6q22.1 associated with ulcerative colitis.
    EBI GWAS Catalog
    Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
    EBI GWAS Catalog

    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

    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 6-phosphofructo-2-kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables 6-phosphofructo-2-kinase activity NAS
    Non-traceable Author Statement
    more info
    		 PubMed 
    enables ATP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables fructose-2,6-bisphosphate 2-phosphatase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    Process Evidence Code Pubs
    involved_in carbohydrate phosphorylation IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in fructose 2,6-bisphosphate metabolic process IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in fructose metabolic process IEA
    Inferred from Electronic Annotation
    more info
    		  
    Component Evidence Code Pubs
    is_active_in cytosol IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in cytosol TAS
    Traceable Author Statement
    more info
    		  

    General protein information

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    Preferred Names
    6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4
    Names
    6PF-2-K/Fru-2,6-P2ase 4
    6PF-2-K/Fru-2,6-P2ase testis-type isozyme
    PFK/FBPase 4
    bifunctional enzyme with kinase and biphosphatase activities
    NP_001304063.1
    NP_001304064.1
    NP_001304065.1
    NP_001304066.1
    NP_001304067.1
    NP_004558.1
    XP_011532131.1
    XP_016862103.1
    XP_016862104.1
    XP_016862105.1
    XP_016862106.1
    XP_024309363.1
    XP_047304256.1
    XP_047304257.1
    XP_047304258.1
    XP_047304259.1
    XP_047304260.1
    XP_054202802.1
    XP_054202803.1
    XP_054202804.1
    XP_054202805.1
    XP_054202806.1
    XP_054202807.1
    XP_054202808.1
    XP_054202809.1
    XP_054202810.1
    XP_054202811.1
    XP_054202812.1

    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.

    mRNA and Protein(s)

    1. NM_001317134.2 → NP_001304063.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform a

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (a).
      Source sequence(s)
      AC134772, AY714243, BC010269
      UniProtKB/TrEMBL
      B2R6L2
      Conserved Domains (3) summary
      pfam00300
      Location:281 → 464
      His_Phos_1; Histidine phosphatase superfamily (branch 1)
      pfam01591
      Location:64 → 278
      6PF2K; 6-phosphofructo-2-kinase
      pfam13671
      Location:70 → 225
      AAA_33; AAA domain

    2. NM_001317135.2 → NP_001304064.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform c

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks an alternate coding exon in the 5' end and uses an alternate in-frame splice junction compared to variant 1. The resulting isoform (c) has a shorter and distinct N-terminus and lacks an alternate internal segment compared to isoform a.
      Source sequence(s)
      AY707863, BC010269
      Consensus CDS
      CCDS82770.1
      UniProtKB/TrEMBL
      B2R6L2, Q66S35
      Related
      ENSP00000388394.1, ENST00000416568.5
      Conserved Domains (2) summary
      pfam01591
      Location:30 → 249
      6PF2K; 6-phosphofructo-2-kinase
      pfam00300
      Location:252 → 431
      His_Phos_1; Histidine phosphatase superfamily (branch 1)

    3. NM_001317136.2 → NP_001304065.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform d

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) uses an alternate first exon in place of the first two exons compared to variant 1. The resulting isoform (d) has a shorter and distinct N-terminus compared to isoform a.
      Source sequence(s)
      AK298732, BC010269
      UniProtKB/TrEMBL
      B2R6L2, B7Z5C3
      Conserved Domains (3) summary
      pfam00300
      Location:241 → 424
      His_Phos_1; Histidine phosphatase superfamily (branch 1)
      pfam01591
      Location:24 → 238
      6PF2K; 6-phosphofructo-2-kinase
      pfam13671
      Location:30 → 185
      AAA_33; AAA domain

    4. NM_001317137.2 → NP_001304066.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform e

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) lacks an alternate coding exon in the 5' end and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (e) has a shorter and distinct N-terminus and lacks an alternate internal segment compared to isoform a.
      Source sequence(s)
      AY756064, BC010269
      Consensus CDS
      CCDS82769.1
      UniProtKB/TrEMBL
      B2R6L2
      Related
      ENSP00000373240.2, ENST00000383734.6
      Conserved Domains (2) summary
      cd07067
      Location:252 → 402
      HP_PGM_like; Histidine phosphatase domain found in phosphoglycerate mutases and related proteins, mostly phosphatases; contains a His residue which is phosphorylated during the reaction
      pfam01591
      Location:30 → 249
      6PF2K; 6-phosphofructo-2-kinase

    5. NM_001317138.2 → NP_001304067.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform f

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) lacks an alternate exon in the 5' end and contains another alternate internal exon compared to variant 1. The resulting isoform (f) is shorter at the N-terminus compared to isoform a.
      Source sequence(s)
      AY756063, BC010269
      UniProtKB/TrEMBL
      Q5XLC3
      Conserved Domains (2) summary
      pfam00300
      Location:61 → 244
      His_Phos_1; Histidine phosphatase superfamily (branch 1)
      cl17190
      Location:1 → 58
      NK; Nucleoside/nucleotide kinase (NK) is a protein superfamily consisting of multiple families of enzymes that share structural similarity and are functionally related to the catalysis of the reversible phosphate group transfer from nucleoside triphosphates ...

    6. NM_004567.4 → NP_004558.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform b

      See identical proteins and their annotated locations for NP_004558.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an alternate coding exon in the 5' end compared to variant 1. The resulting isoform (b) has a shorter and distinct N-terminus compared to isoform a.
      Source sequence(s)
      BC010269, DB069657
      Consensus CDS
      CCDS2771.1
      UniProtKB/Swiss-Prot
      Q16877, Q5S3G5, Q5XLC2, Q64EX5
      UniProtKB/TrEMBL
      B2R6L2
      Related
      ENSP00000232375.3, ENST00000232375.8
      Conserved Domains (2) summary
      pfam01591
      Location:30 → 249
      6PF2K; 6-phosphofructo-2-kinase
      pfam00300
      Location:252 → 438
      His_Phos_1; Histidine phosphatase superfamily (branch 1)

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

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

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000003.12 Reference GRCh38.p14 Primary Assembly

      Range
      48517684..48563136 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_011533829.3 → XP_011532131.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X2

      UniProtKB/TrEMBL
      B2R6L2
      Conserved Domains (3) summary
      pfam00300
      Location:254 → 437
      His_Phos_1; Histidine phosphatase superfamily (branch 1)
      pfam01591
      Location:37 → 251
      6PF2K; 6-phosphofructo-2-kinase
      pfam13671
      Location:43 → 198
      AAA_33; AAA domain

    2. XM_047448304.1 → XP_047304260.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X9

    3. XM_017006617.2 → XP_016862106.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X6

      UniProtKB/TrEMBL
      B2R6L2

    4. XM_047448301.1 → XP_047304257.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X7

    5. XM_017006616.2 → XP_016862105.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X5

      UniProtKB/TrEMBL
      B2R6L2

    6. XM_047448302.1 → XP_047304258.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

    7. XM_047448300.1 → XP_047304256.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X3

    8. XM_017006615.2 → XP_016862104.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X4

      UniProtKB/TrEMBL
      B2R6L2

    9. XM_017006614.2 → XP_016862103.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X1

      UniProtKB/TrEMBL
      B2R6L2

    10. XM_047448303.1 → XP_047304259.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

    11. XM_024453595.2 → XP_024309363.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

      UniProtKB/TrEMBL
      B2R6L2
      Conserved Domains (2) summary
      pfam01591
      Location:1 → 215
      6PF2K; 6-phosphofructo-2-kinase
      pfam00300
      Location:218 → 404
      His_Phos_1; Histidine phosphatase superfamily (branch 1)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060927.1 Alternate T2T-CHM13v2.0

      Range
      48546648..48592093 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054346828.1 → XP_054202803.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X2

    2. XM_054346837.1 → XP_054202812.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X9

    3. XM_054346832.1 → XP_054202807.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X6

    4. XM_054346833.1 → XP_054202808.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X7

    5. XM_054346831.1 → XP_054202806.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X5

    6. XM_054346834.1 → XP_054202809.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

    7. XM_054346829.1 → XP_054202804.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X3

    8. XM_054346830.1 → XP_054202805.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X4

    9. XM_054346827.1 → XP_054202802.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X1

    10. XM_054346836.1 → XP_054202811.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

    11. XM_054346835.1 → XP_054202810.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q16877.6 GenPept UniProtKB/Swiss-Prot:Q16877

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