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Protein

Sepiapterin reductase

Gene

SPR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.

Catalytic activityi

L-erythro-7,8-dihydrobiopterin + NADP+ = sepiapterin + NADPH.
L-erythro-tetrahydrobiopterin + 2 NADP+ = 6-pyruvoyl-5,6,7,8-tetrahydropterin + 2 NADPH.

Kineticsi

  1. KM=14.3 µM for sepiapterin1 Publication
  2. KM=10 µM for NADPH1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei170SubstrateBy similarity1
    Binding sitei174NADPBy similarity1
    Binding sitei199Substrate; via amide nitrogenBy similarity1
    Binding sitei257SubstrateBy similarity1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi14 – 20NADP1 Publication7
    Nucleotide bindingi42 – 43NADP1 Publication2
    Nucleotide bindingi69 – 70NADP1 Publication2
    Nucleotide bindingi201 – 206NADP1 Publication6

    GO - Molecular functioni

    • aldo-keto reductase (NADP) activity Source: UniProtKB
    • NADP binding Source: UniProtKB
    • sepiapterin reductase activity Source: UniProtKB

    GO - Biological processi

    • cofactor metabolic process Source: Reactome
    • nitric oxide biosynthetic process Source: UniProtKB
    • oxidation-reduction process Source: UniProtKB
    • regulation of nitric-oxide synthase activity Source: Reactome
    • tetrahydrobiopterin biosynthetic process Source: GO_Central

    Keywordsi

    Molecular functionOxidoreductase
    LigandNADP

    Enzyme and pathway databases

    BioCyciMetaCyc:HS03979-MONOMER
    ReactomeiR-HSA-1474151 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
    R-HSA-203615 eNOS activation
    SIGNORiP35270

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Sepiapterin reductase (EC:1.1.1.153)
    Short name:
    SPR
    Gene namesi
    Name:SPR
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 2

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000116096.5
    HGNCiHGNC:11257 SPR
    MIMi182125 gene
    neXtProtiNX_P35270

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Involvement in diseasei

    Dystonia, DOPA-responsive, due to sepiapterin reductase deficiency (DRDSPRD)3 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA form of DOPA-responsive dystonia. In the majority of cases, patients manifest progressive psychomotor retardation, dystonia and spasticity. Cognitive anomalies are also often present. The disease is due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures.
    See also OMIM:612716
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_058007150R → G in DRDSPRD. 2 PublicationsCorresponds to variant dbSNP:rs104893665EnsemblClinVar.1
    Natural variantiVAR_058008163P → L in DRDSPRD. 1 PublicationCorresponds to variant dbSNP:rs104893666EnsemblClinVar.1

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi213S → A: Abolishes phosphorylation by CaMK2. No effect on kinetic parameters. 1 Publication1

    Keywords - Diseasei

    Disease mutation, Dystonia

    Organism-specific databases

    DisGeNETi6697
    MalaCardsiSPR
    MIMi612716 phenotype
    OpenTargetsiENSG00000116096
    Orphaneti70594 Dopa-responsive dystonia due to sepiapterin reductase deficiency
    PharmGKBiPA36087

    Chemistry databases

    ChEMBLiCHEMBL3988583
    DrugBankiDB03461 2'-Monophosphoadenosine 5'-Diphosphoribose
    DB03886 Biopterin
    DB04275 N-Acetyl Serotonin
    DB02637 Oxaloacetate Ion

    Polymorphism and mutation databases

    BioMutaiSPR
    DMDMi464801

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000721491 – 261Sepiapterin reductaseAdd BLAST261

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei1N-acetylmethionineBy similarity1
    Modified residuei32PhosphoserineBy similarity1
    Modified residuei103PhosphoserineCombined sources1
    Modified residuei213Phosphoserine; by CaMK2; in vitro1 Publication1

    Post-translational modificationi

    In vitro phosphorylation of Ser-213 by CaMK2 does not change kinetic parameters.1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    EPDiP35270
    MaxQBiP35270
    PaxDbiP35270
    PeptideAtlasiP35270
    PRIDEiP35270
    ProteomicsDBi55020

    PTM databases

    iPTMnetiP35270
    PhosphoSitePlusiP35270

    Expressioni

    Gene expression databases

    BgeeiENSG00000116096 Expressed in 200 organ(s), highest expression level in mucosa of transverse colon
    CleanExiHS_SPR
    GenevisibleiP35270 HS

    Organism-specific databases

    HPAiHPA039505

    Interactioni

    Subunit structurei

    Homodimer.1 Publication

    Protein-protein interaction databases

    BioGridi112575, 48 interactors
    IntActiP35270, 1 interactor
    MINTiP35270
    STRINGi9606.ENSP00000234454

    Chemistry databases

    BindingDBiP35270

    Structurei

    Secondary structure

    1261
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliP35270
    SMRiP35270
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP35270

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni157 – 158Substrate bindingBy similarity2

    Sequence similaritiesi

    Belongs to the sepiapterin reductase family.Curated

    Phylogenomic databases

    eggNOGiKOG1204 Eukaryota
    ENOG4111PZG LUCA
    GeneTreeiENSGT00440000033609
    HOVERGENiHBG006973
    InParanoidiP35270
    KOiK00072
    OMAiTFKSGAH
    OrthoDBiEOG091G0N30
    PhylomeDBiP35270
    TreeFamiTF326358

    Family and domain databases

    InterProiView protein in InterPro
    IPR036291 NAD(P)-bd_dom_sf
    IPR002347 SDR_fam
    IPR006393 Sepiapterin_red
    PfamiView protein in Pfam
    PF00106 adh_short, 1 hit
    PRINTSiPR00081 GDHRDH
    SUPFAMiSSF51735 SSF51735, 1 hit
    TIGRFAMsiTIGR01500 sepiapter_red, 1 hit

    Sequencei

    Sequence statusi: Complete.

    P35270-1 [UniParc]FASTAAdd to basket
    « Hide
            10         20         30         40         50
    MEGGLGRAVC LLTGASRGFG RTLAPLLASL LSPGSVLVLS ARNDEALRQL
    60 70 80 90 100
    EAELGAERSG LRVVRVPADL GAEAGLQQLL GALRELPRPK GLQRLLLINN
    110 120 130 140 150
    AGSLGDVSKG FVDLSDSTQV NNYWALNLTS MLCLTSSVLK AFPDSPGLNR
    160 170 180 190 200
    TVVNISSLCA LQPFKGWALY CAGKAARDML FQVLALEEPN VRVLNYAPGP
    210 220 230 240 250
    LDTDMQQLAR ETSVDPDMRK GLQELKAKGK LVDCKVSAQK LLSLLEKDEF
    260
    KSGAHVDFYD K
    Length:261
    Mass (Da):28,048
    Last modified:February 1, 1994 - v1
    Checksum:i9C9BF76212826F47
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti10C → R in BAD96662 (Ref. 4) Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_058007150R → G in DRDSPRD. 2 PublicationsCorresponds to variant dbSNP:rs104893665EnsemblClinVar.1
    Natural variantiVAR_058008163P → L in DRDSPRD. 1 PublicationCorresponds to variant dbSNP:rs104893666EnsemblClinVar.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M76231 mRNA Translation: AAA60314.1
    AK291856 mRNA Translation: BAF84545.1
    AK222942 mRNA Translation: BAD96662.1
    AC092630 Genomic DNA Translation: AAY15035.1
    CH471053 Genomic DNA Translation: EAW99757.1
    CH471053 Genomic DNA Translation: EAW99758.1
    BC017310 mRNA Translation: AAH17310.1
    AB017547 Genomic DNA Translation: BAA34534.1
    CCDSiCCDS1920.1
    PIRiJQ1176
    RefSeqiNP_003115.1, NM_003124.4
    UniGeneiHs.301540

    Genome annotation databases

    EnsembliENST00000234454; ENSP00000234454; ENSG00000116096
    GeneIDi6697
    KEGGihsa:6697
    UCSCiuc002sik.3 human

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M76231 mRNA Translation: AAA60314.1
    AK291856 mRNA Translation: BAF84545.1
    AK222942 mRNA Translation: BAD96662.1
    AC092630 Genomic DNA Translation: AAY15035.1
    CH471053 Genomic DNA Translation: EAW99757.1
    CH471053 Genomic DNA Translation: EAW99758.1
    BC017310 mRNA Translation: AAH17310.1
    AB017547 Genomic DNA Translation: BAA34534.1
    CCDSiCCDS1920.1
    PIRiJQ1176
    RefSeqiNP_003115.1, NM_003124.4
    UniGeneiHs.301540

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1Z6ZX-ray2.50A/B/C/D/E/F5-261[»]
    4HWKX-ray2.40A/B/C/D1-261[»]
    4J7UX-ray2.44A/B/C/D1-261[»]
    4J7XX-ray2.60A/B/F/J1-261[»]
    4XWYX-ray2.35A/B/C/D1-261[»]
    4Z3KX-ray2.35A/B/C/D1-261[»]
    ProteinModelPortaliP35270
    SMRiP35270
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi112575, 48 interactors
    IntActiP35270, 1 interactor
    MINTiP35270
    STRINGi9606.ENSP00000234454

    Chemistry databases

    BindingDBiP35270
    ChEMBLiCHEMBL3988583
    DrugBankiDB03461 2'-Monophosphoadenosine 5'-Diphosphoribose
    DB03886 Biopterin
    DB04275 N-Acetyl Serotonin
    DB02637 Oxaloacetate Ion

    PTM databases

    iPTMnetiP35270
    PhosphoSitePlusiP35270

    Polymorphism and mutation databases

    BioMutaiSPR
    DMDMi464801

    Proteomic databases

    EPDiP35270
    MaxQBiP35270
    PaxDbiP35270
    PeptideAtlasiP35270
    PRIDEiP35270
    ProteomicsDBi55020

    Protocols and materials databases

    DNASUi6697
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000234454; ENSP00000234454; ENSG00000116096
    GeneIDi6697
    KEGGihsa:6697
    UCSCiuc002sik.3 human

    Organism-specific databases

    CTDi6697
    DisGeNETi6697
    EuPathDBiHostDB:ENSG00000116096.5
    GeneCardsiSPR
    HGNCiHGNC:11257 SPR
    HPAiHPA039505
    MalaCardsiSPR
    MIMi182125 gene
    612716 phenotype
    neXtProtiNX_P35270
    OpenTargetsiENSG00000116096
    Orphaneti70594 Dopa-responsive dystonia due to sepiapterin reductase deficiency
    PharmGKBiPA36087
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG1204 Eukaryota
    ENOG4111PZG LUCA
    GeneTreeiENSGT00440000033609
    HOVERGENiHBG006973
    InParanoidiP35270
    KOiK00072
    OMAiTFKSGAH
    OrthoDBiEOG091G0N30
    PhylomeDBiP35270
    TreeFamiTF326358

    Enzyme and pathway databases

    BioCyciMetaCyc:HS03979-MONOMER
    ReactomeiR-HSA-1474151 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
    R-HSA-203615 eNOS activation
    SIGNORiP35270

    Miscellaneous databases

    ChiTaRSiSPR human
    EvolutionaryTraceiP35270
    GeneWikiiSepiapterin_reductase
    GenomeRNAii6697
    PROiPR:P35270
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000116096 Expressed in 200 organ(s), highest expression level in mucosa of transverse colon
    CleanExiHS_SPR
    GenevisibleiP35270 HS

    Family and domain databases

    InterProiView protein in InterPro
    IPR036291 NAD(P)-bd_dom_sf
    IPR002347 SDR_fam
    IPR006393 Sepiapterin_red
    PfamiView protein in Pfam
    PF00106 adh_short, 1 hit
    PRINTSiPR00081 GDHRDH
    SUPFAMiSSF51735 SSF51735, 1 hit
    TIGRFAMsiTIGR01500 sepiapter_red, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiSPRE_HUMAN
    AccessioniPrimary (citable) accession number: P35270
    Secondary accession number(s): A8K741
    , D6W5H2, Q53GI9, Q9UBB1
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1994
    Last sequence update: February 1, 1994
    Last modified: November 7, 2018
    This is version 186 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny 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.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families
    2. Human chromosome 2
      Human chromosome 2: entries, gene names and cross-references to MIM
    3. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    4. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    5. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health

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