SPRE_RAT
ID SPRE_RAT Reviewed; 262 AA.
AC P18297;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1990, sequence version 1.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Sepiapterin reductase;
DE Short=SPR;
DE EC=1.1.1.153 {ECO:0000269|PubMed:10350607};
GN Name=Spr;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2201030; DOI=10.1073/pnas.87.16.6436;
RA Citron B.A., Milstien S., Gutierrez J.C., Levine R.A., Yanak B.L.,
RA Kaufman S.;
RT "Isolation and expression of rat liver sepiapterin reductase cDNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:6436-6440(1990).
RN [2]
RP PROTEIN SEQUENCE, AND ACETYLATION AT MET-1.
RX PubMed=2260974; DOI=10.1016/s0006-291x(05)80081-6;
RA Oyama R., Katoh S., Sueoka T., Suzuki M., Ichinose H., Nagatsu T.,
RA Titani K.;
RT "The complete amino acid sequence of the mature form of rat sepiapterin
RT reductase.";
RL Biochem. Biophys. Res. Commun. 173:627-631(1990).
RN [3]
RP MUTAGENESIS OF ALA-29; SER-158; TYR-171 AND LYS-175, CATALYTIC ACTIVITY,
RP AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=10350607; DOI=10.1016/s0167-4838(99)00054-0;
RA Fujimoto K., Ichinose H., Nagatsu T., Nonaka T., Mitsui Y., Katoh S.;
RT "Functionally important residues tyrosine-171 and serine-158 in sepiapterin
RT reductase.";
RL Biochim. Biophys. Acta 1431:306-314(1999).
RN [4]
RP KINETIC PARAMETERS, PHOSPHORYLATION AT SER-46; SER-196 AND SER-214, AND
RP MUTAGENESIS OF SER-46; SER-196 AND SER-214.
RX PubMed=11825621; DOI=10.1016/s0167-4838(01)00300-4;
RA Fujimoto K., Takahashi S.Y., Katoh S.;
RT "Mutational analysis of sites in sepiapterin reductase phosphorylated by
RT Ca2+/calmodulin-dependent protein kinase II.";
RL Biochim. Biophys. Acta 1594:191-198(2002).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-33, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: Catalyzes the final one or two reductions in tetra-
CC hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-erythro-7,8-dihydrobiopterin + NADP(+) = H(+) + NADPH +
CC sepiapterin; Xref=Rhea:RHEA:18953, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16095, ChEBI:CHEBI:43029, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.1.1.153;
CC Evidence={ECO:0000269|PubMed:10350607};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18955;
CC Evidence={ECO:0000269|PubMed:10350607};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + 2 NADP(+) = 6-
CC pyruvoyl-5,6,7,8-tetrahydropterin + 2 H(+) + 2 NADPH;
CC Xref=Rhea:RHEA:32627, ChEBI:CHEBI:15378, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:59560, ChEBI:CHEBI:136564;
CC EC=1.1.1.153; Evidence={ECO:0000305|PubMed:10350607};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:32629;
CC Evidence={ECO:0000305|PubMed:10350607};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=12.6 uM for sepiapterin {ECO:0000269|PubMed:10350607,
CC ECO:0000269|PubMed:11825621};
CC KM=2.8 uM for NADPH {ECO:0000269|PubMed:10350607,
CC ECO:0000269|PubMed:11825621};
CC Note=kcat is 9.7 sec(-1) with sepiapterin as substrate
CC (PubMed:10350607). kcat is 11.1 sec(-1) with NADPH as substrate
CC (PubMed:10350607). {ECO:0000269|PubMed:10350607};
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- PTM: In vitro phosphorylation of Ser-46, Ser-196 and Ser-214 by CaMK2
CC does not change kinetic parameters. {ECO:0000269|PubMed:11825621}.
CC -!- SIMILARITY: Belongs to the sepiapterin reductase family. {ECO:0000305}.
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DR EMBL; M36410; AAA42130.1; -; mRNA.
DR PIR; A36024; A36024.
DR RefSeq; NP_062054.1; NM_019181.1.
DR AlphaFoldDB; P18297; -.
DR SMR; P18297; -.
DR STRING; 10116.ENSRNOP00000020749; -.
DR iPTMnet; P18297; -.
DR PhosphoSitePlus; P18297; -.
DR jPOST; P18297; -.
DR PaxDb; P18297; -.
DR PRIDE; P18297; -.
DR Ensembl; ENSRNOT00000020749; ENSRNOP00000020749; ENSRNOG00000015455.
DR GeneID; 29270; -.
DR KEGG; rno:29270; -.
DR UCSC; RGD:3753; rat.
DR CTD; 6697; -.
DR RGD; 3753; Spr.
DR eggNOG; KOG1204; Eukaryota.
DR GeneTree; ENSGT00440000033609; -.
DR HOGENOM; CLU_010194_2_11_1; -.
DR InParanoid; P18297; -.
DR OMA; MTVQVQR; -.
DR OrthoDB; 1089743at2759; -.
DR PhylomeDB; P18297; -.
DR TreeFam; TF326358; -.
DR BRENDA; 1.1.1.153; 5301.
DR Reactome; R-RNO-1474151; Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
DR Reactome; R-RNO-203615; eNOS activation.
DR SABIO-RK; P18297; -.
DR PRO; PR:P18297; -.
DR Proteomes; UP000002494; Chromosome 4.
DR Bgee; ENSRNOG00000015455; Expressed in liver and 19 other tissues.
DR ExpressionAtlas; P18297; baseline and differential.
DR Genevisible; P18297; RN.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0004757; F:sepiapterin reductase activity; IDA:UniProtKB.
DR GO; GO:0048667; P:cell morphogenesis involved in neuron differentiation; ISO:RGD.
DR GO; GO:0042417; P:dopamine metabolic process; ISO:RGD.
DR GO; GO:0006558; P:L-phenylalanine metabolic process; ISO:RGD.
DR GO; GO:0006809; P:nitric oxide biosynthetic process; ISO:RGD.
DR GO; GO:0042415; P:norepinephrine metabolic process; ISO:RGD.
DR GO; GO:0019889; P:pteridine metabolic process; ISO:RGD.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISO:RGD.
DR GO; GO:0010033; P:response to organic substance; IMP:RGD.
DR GO; GO:0042428; P:serotonin metabolic process; ISO:RGD.
DR GO; GO:0006729; P:tetrahydrobiopterin biosynthetic process; IMP:RGD.
DR GO; GO:0046146; P:tetrahydrobiopterin metabolic process; ISO:RGD.
DR GO; GO:0050882; P:voluntary musculoskeletal movement; ISO:RGD.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR002347; SDR_fam.
DR InterPro; IPR006393; Sepiapterin_red.
DR Pfam; PF00106; adh_short; 1.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
DR TIGRFAMs; TIGR01500; sepiapter_red; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; Direct protein sequencing; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..262
FT /note="Sepiapterin reductase"
FT /id="PRO_0000072151"
FT BINDING 15..21
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 43..44
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 70..71
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 158..159
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 171
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 175
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 200
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 202..207
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 258
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000269|PubMed:2260974"
FT MOD_RES 33
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 46
FT /note="Phosphoserine; by CaMK2; in vitro"
FT /evidence="ECO:0000269|PubMed:11825621"
FT MOD_RES 196
FT /note="Phosphoserine; by CaMK2; in vitro"
FT /evidence="ECO:0000269|PubMed:11825621"
FT MOD_RES 214
FT /note="Phosphoserine; by CaMK2; in vitro"
FT /evidence="ECO:0000269|PubMed:11825621"
FT MUTAGEN 29
FT /note="A->V: Reduces affinity for NADP and for sepiapterin
FT 4-fold."
FT /evidence="ECO:0000269|PubMed:10350607"
FT MUTAGEN 46
FT /note="S->A: Abolishes phosphorylation by CaMK2. No effect
FT on kinetic parameters; when associated with A-196 and A-
FT 214."
FT /evidence="ECO:0000269|PubMed:11825621"
FT MUTAGEN 158
FT /note="S->D: Reduces activity 4-fold. Loss of activity;
FT when associated with V-171."
FT /evidence="ECO:0000269|PubMed:10350607"
FT MUTAGEN 171
FT /note="Y->V: Reduces activity 4-fold. Loss of activity;
FT when associated with V-171."
FT /evidence="ECO:0000269|PubMed:10350607"
FT MUTAGEN 175
FT /note="K->I: Reduces activity 4-fold."
FT /evidence="ECO:0000269|PubMed:10350607"
FT MUTAGEN 196
FT /note="S->A: Abolishes phosphorylation by CaMK2. No effect
FT on kinetic parameters; when associated with A-46 and A-
FT 214."
FT /evidence="ECO:0000269|PubMed:11825621"
FT MUTAGEN 214
FT /note="S->A: Abolishes phosphorylation by CaMK2. No effect
FT on kinetic parameters; when associated with A-46 and A-
FT 196."
FT /evidence="ECO:0000269|PubMed:11825621"
SQ SEQUENCE 262 AA; 28128 MW; EC992564A0334C61 CRC64;
MEGGRLGCAV CVLTGASRGF GRALAPQLAG LLSPGSVLLL SARSDSMLRQ LKEELCTQQP
GLQVVLAAAD LGTESGVQQL LSAVRELPRP ERLQRLLLIN NAGTLGDVSK GFLNINDLAE
VNNYWALNLT SMLCLTTGTL NAFSNSPGLS KTVVNISSLC ALQPFKGWGL YCAGKAARDM
LYQVLAVEEP SVRVLSYAPG PLDTNMQQLA RETSMDPELR SRLQKLNSEG ELVDCGTSAQ
KLLSLLQRDT FQSGAHVDFY DI
