P35270 (SPRE_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Sepiapterin reductase
Short name=SPR
EC=1.1.1.153

Gene names

Name:

SPR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	261 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
Catalytic activity	7,8-dihydrobiopterin + NADP+ = sepiapterin + NADPH. Tetrahydrobiopterin + 2 NADP+ = 6-pyruvoyl-5,6,7,8-tetrahydropterin + 2 NADPH.
Subunit structure	Homodimer.
Subcellular location	Cytoplasm.
Post-translational modification	In vitro phosphorylation of Ser-213 by CaMK2 does not change kinetic parameters.
Involvement in disease	Defects in SPR are the cause of dystonia DOPA-responsive due to sepiapterin reductase deficiency (DRDSPRD) [MIM:612716]. 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. Ref.12 Ref.13 Ref.14
Sequence similarities	Belongs to the sepiapterin reductase family.
Biophysicochemical properties	Kinetic parameters: KM=14.3 µM for sepiapterin Ref.9 KM=10 µM for NADPH

Ontologies

Keywords
Cellular component	Cytoplasm
Disease	Disease mutation Dystonia
Ligand	NADP
Molecular function	Oxidoreductase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	nitric oxide biosynthetic process Inferred from direct assay. Source: UniProtKB tetrahydrobiopterin biosynthetic process Traceable author statement Ref.1. Source: UniProtKB
Cellular component	cytoplasm Inferred from direct assay. Source: HPA nucleus Inferred from direct assay. Source: HPA
Molecular function	NADP binding Traceable author statement Ref.1. Source: UniProtKB aldo-keto reductase (NADP) activity Traceable author statement Ref.1. Source: UniProtKB sepiapterin reductase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 261

261

Sepiapterin reductase

PRO_0000072149

Regions

Nucleotide binding

14 – 20

7

NADP

Nucleotide binding

42 – 43

2

NADP

Nucleotide binding

69 – 70

2

NADP

Nucleotide binding

201 – 206

6

NADP

Region

157 – 158

2

Substrate binding By similarity

Sites

Binding site

170

1

Substrate By similarity

Binding site

174

1

NADP By similarity

Binding site

199

1

Substrate; via amide nitrogen By similarity

Binding site

257

1

Substrate By similarity

Amino acid modifications

Modified residue

1

1

N-acetylmethionine By similarity

Modified residue

213

1

Phosphoserine; by CaMK2; in vitro Ref.9

Natural variations

Natural variant

150

1

R → G in DRDSPRD. Ref.12 Ref.14

VAR_058007

Natural variant

163

1

P → L in DRDSPRD. Ref.13

VAR_058008

Experimental info

Mutagenesis

213

1

S → A: Abolishes phosphorylation by CaMK2. No effect on kinetic parameters. Ref.9

Sequence conflict

10

1

C → R in BAD96662. Ref.4

Secondary structure

1

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261

Helix Strand Turn

Details...

Beta strand

6 – 14

9

Helix

18 – 28

11

Beta strand

36 – 42

7

Helix

44 – 52

9

Helix

56 – 59

4

Beta strand

62 – 67

6

Helix

73 – 84

12

Beta strand

94 – 99

6

Helix

111 – 113

3

Helix

117 – 127

11

Helix

129 – 141

13

Beta strand

149 – 155

7

Helix

158 – 160

3

Helix

168 – 187

20

Beta strand

191 – 197

7

Beta strand

200 – 203

4

Helix

204 – 212

9

Helix

216 – 227

12

Helix

234 – 247

14

Beta strand

255 – 257

3

Sequences

	Sequence		Length	Mass (Da)
	P35270 [UniParc]. Last modified February 1, 1994. Version 1. Checksum: 9C9BF76212826F47	FASTA	261	28,048
	10 20 30 40 50 60 MEGGLGRAVC LLTGASRGFG RTLAPLLASL LSPGSVLVLS ARNDEALRQL EAELGAERSG 70 80 90 100 110 120 LRVVRVPADL GAEAGLQQLL GALRELPRPK GLQRLLLINN AGSLGDVSKG FVDLSDSTQV 130 140 150 160 170 180 NNYWALNLTS MLCLTSSVLK AFPDSPGLNR TVVNISSLCA LQPFKGWALY CAGKAARDML 190 200 210 220 230 240 FQVLALEEPN VRVLNYAPGP LDTDMQQLAR ETSVDPDMRK GLQELKAKGK LVDCKVSAQK 250 260 LLSLLEKDEF KSGAHVDFYD K

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and sequencing of cDNA encoding human sepiapterin reductase -- an enzyme involved in tetrahydrobiopterin biosynthesis." Ichinose H., Katoh S., Sueoka T., Titani K., Fujita K., Nagatsu T. Biochem. Biophys. Res. Commun. 179:183-189(1991) [PubMed: 1883349] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"Detection of a novel sepiapterin reductase mRNA: assay of mRNA in various cells and tissues of various species." Maier J., Schott K., Werner T., Bacher A., Ziegler I. Exp. Cell Res. 204:217-222(1993) [PubMed: 8440319] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Salivary gland.
[4]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Kidney.
[5]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed: 15815621] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[8]	"Genomic organization and chromosomal localization of the human sepiapterin reductase gene." Ohye T., Hori T.A., Katoh S., Nagatsu T., Ichinose H. Biochem. Biophys. Res. Commun. 251:597-602(1998) [PubMed: 9792819] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[9]	"Mutational analysis of sites in sepiapterin reductase phosphorylated by Ca2+/calmodulin-dependent protein kinase II." Fujimoto K., Takahashi S.Y., Katoh S. Biochim. Biophys. Acta 1594:191-198(2002) [PubMed: 11825621] [Abstract] Cited for: KINETIC PARAMETERS, PHOSPHORYLATION AT SER-213, MUTAGENESIS OF SER-213.
[10]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]	"Crystal structure of human sepiapterin reductase." Structural genomics consortium (SGC) Submitted (FEB-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 5-261 IN COMPLEX WITH NADP.
[12]	"Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia." Bonafe L., Thony B., Penzien J.M., Czarnecki B., Blau N. Am. J. Hum. Genet. 69:269-277(2001) [PubMed: 11443547] [Abstract] Cited for: VARIANT DRDSPRD GLY-150.
[13]	"Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia." Abeling N.G.G.M., Duran M., Bakker H.D., Stroomer L., Thoeny B., Blau N., Booij J., Poll-The B.T. Mol. Genet. Metab. 89:116-120(2006) [PubMed: 16650784] [Abstract] Cited for: VARIANT DRDSPRD LEU-163.
[14]	"Dopa-responsive hypersomnia and mixed movement disorder due to sepiapterin reductase deficiency." Friedman J., Hyland K., Blau N., MacCollin M. Neurology 67:2032-2035(2006) [PubMed: 17159114] [Abstract] Cited for: VARIANT DRDSPRD GLY-150.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00017469.

PIR

JQ1176.

RefSeq

NP_003115.1. NM_003124.4.

UniGene

Hs.301540.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1Z6Z	X-ray	2.50	A/B/C/D/E/F	5-261	[»]

ProteinModelPortal

P35270.

SMR

P35270. Positions 5-261.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-3304575.

STRING

P35270.

PTM databases

PhosphoSite

P35270.

Polymorphism databases

DMDM

464801.

Proteomic databases

PeptideAtlas

P35270.

PRIDE

P35270.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000234454; ENSP00000234454; ENSG00000116096.

GeneID

6697.

KEGG

hsa:6697.

NMPDR

fig|9606.3.peg.18026.

UCSC

uc002sik.2. human.

Organism-specific databases

CTD

6697.

GeneCards

GC02P073026.

H-InvDB

HIX0002155.

HGNC

HGNC:11257. SPR.

HPA

HPA039505.

MIM

182125. gene.
612716. phenotype.

neXtProt

NX_P35270.

Orphanet

70594. Motor and cognitive disorder due to sepiapterin reductase deficiency.

PharmGKB

PA36087.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG14279.

HOGENOM

HBG622863.

HOVERGEN

HBG006973.

InParanoid

P35270.

OMA

AGVVEPI.

OrthoDB

EOG4HMJB9.

PhylomeDB

P35270.

Enzyme and pathway databases

BioCyc

MetaCyc:MONOMER-13412.

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P35270.

Bgee

P35270.

CleanEx

HS_SPR.

Genevestigator

P35270.

GermOnline

ENSG00000116096. Homo sapiens.

Family and domain databases

InterPro

IPR002198. DH_sc/Rdtase_SDR.
IPR002347. Glc/ribitol_DH.
IPR016040. NAD(P)-bd_dom.
IPR006393. Sepiapterin_red.
[Graphical view]

Gene3D

G3DSA:3.40.50.720. NAD(P)-bd. 1 hit.

KO

K00072.

Pfam

PF00106. adh_short. 1 hit.
[Graphical view]

PRINTS

PR00081. GDHRDH.

TIGRFAMs

TIGR01500. Sepiapter_red. 1 hit.

ProtoNet

Search...

Other

NextBio

26111.

SOURCE

Search...

Entry information

Entry name

SPRE_HUMAN

Accession

Primary (citable) accession number: P35270
Secondary accession number(s): A8K741 , D6W5H2, Q53GI9, Q9UBB1

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1994
Last sequence update:	February 1, 1994
Last modified:	January 25, 2012
This is version 125 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.