Dihydropteridine reductase - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot P09417 (DHPR_HUMAN)

Last modified June 16, 2009. Version 113. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Dihydropteridine reductase
    EC=1.5.1.34
Alternative name(s):
    HDHPR
    Quinoid dihydropteridine reductase

Gene names

Name:	QDPR
Synonyms:	DHPR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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Protein attributes

Sequence length	244 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	The product of this enzyme, tetrahydrobiopterin (BH-4), is an essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases.
Catalytic activity	A 5,6,7,8-tetrahydropteridine + NAD(P)⁺ = a 6,7-dihydropteridine + NAD(P)H.
Subunit structure	Homodimer.
Involvement in disease	Defects in QDPR are the cause of phenylketonuria II (PK2) [MIM:261630]; also known as dihydropteridine reductase deficiency. PK2 is a rare autosomal recessive disorder characterized by hyperphenylalaninemia and severe neurologic symptoms (malignant hyperphenylalaninemia) including axial hypotonia and truncal hypertonia, abnormal thermogenesis, and microcephaly. These signs are attributable to depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases that use BH-4 as cofactor. These patients do not respond to phenylalanine-restricted diet. PK2 is lethal if untreated. Ref.4 Ref.12 Ref.13 Ref.14 Ref.15
Sequence similarities	Belongs to the short-chain dehydrogenases/reductases (SDR) family.

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Ontologies

Keywords
Biological process	Tetrahydrobiopterin biosynthesis
Coding sequence diversity	Polymorphism
Disease	Disease mutation Phenylketonuria
Ligand	NADP
Molecular function	Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	L-phenylalanine catabolic process Inferred from electronic annotation. Source: UniProtKB-KW dihydrobiopterin metabolic process Ref.3 Traceable author statement. Source: ProtInc oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW tetrahydrobiopterin biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from direct assay. Source: LIFEdb
Molecular function	6,7-dihydropteridine reductase activity Ref.3 Traceable author statement. Source: ProtInc binding Inferred from electronic annotation. Source: InterPro electron carrier activity Ref.3 Traceable author statement. Source: UniProtKB
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

Removed Ref.8

Chain

2 – 244

243

Dihydropteridine reductase

PRO_0000054636

Regions

Nucleotide binding

14 – 38

NADP

Sites

Active site

150

Proton acceptor

Amino acid modifications

Modified residue

N-acetylalanine Ref.8

Natural variations

Natural variant

L → P in PK2; severe. Ref.14

VAR_008121

Natural variant

G → R in PK2; severe. Ref.14 Ref.15

VAR_021767

Natural variant

G → V in PK2; severe. Ref.14 Ref.15

VAR_008122

Natural variant

G → D in PK2; severe. Ref.15

VAR_021768

Natural variant

G → D in PK2; severe. Ref.4 Ref.12 Ref.15

VAR_006960

Natural variant

W → R in PK2.

VAR_006961

Natural variant

S → T Ref.4 Ref.1 Ref.3

VAR_013027

Natural variant

Q → R in PK2; severe. Ref.15

VAR_021769

Natural variant

L → P in PK2.

VAR_006962

Natural variant

108

W → G in PK2. Ref.12

VAR_006963

Natural variant

123

T → TT in PK2. Ref.13

VAR_006964

Natural variant

145

P → L in PK2.

VAR_006965

Natural variant

149

G → R in PK2. Ref.15

VAR_021770

Natural variant

150

Y → C in PK2; mild. Ref.4 Ref.13 Ref.15

VAR_006966

Natural variant

151

G → S in PK2; mild.

VAR_006967

Natural variant

158

H → Y in PK2; severe. Ref.4

VAR_006968

Natural variant

170

G → S in PK2. Ref.4 Ref.13

VAR_006969

Natural variant

212

F → C in PK2; mild.

VAR_006970

Natural variant

218

G → GITG in PK2; mild.

VAR_006971

Secondary structure

244

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P09417-1 [UniParc].

Last modified November 28, 2006. Version 2.
Checksum: 0852F9F0CA38AB1C
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FASTA

244

25,790

        10         20         30         40         50         60 
MAAAAAAGEA RRVLVYGGRG ALGSRCVQAF RARNWWVASV DVVENEEASA SIIVKMTDSF 

        70         80         90        100        110        120 
TEQADQVTAE VGKLLGEEKV DAILCVAGGW AGGNAKSKSL FKNCDLMWKQ SIWTSTISSH 

       130        140        150        160        170        180 
LATKHLKEGG LLTLAGAKAA LDGTPGMIGY GMAKGAVHQL CQSLAGKNSG MPPGAAAIAV 

       190        200        210        220        230        240 
LPVTLDTPMN RKSMPEADFS SWTPLEFLVE TFHDWITGKN RPSSGSLIQV VTTEGRTELT 


PAYF

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human dihydropteridine reductase: characterisation of a cDNA clone and its use in analysis of patients with dihydropteridine reductase deficiency." Dahl H.-H.M., Hutchison W., McAdam W., Wake S., Morgan F.J., Cotton R.G.H. Nucleic Acids Res. 15:1921-1932(1987) [PubMed: 3031582] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT THR-51.
[2]	Dahl H.-H.M. Submitted (JUL-1987) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO 51.
[3]	"Structure and expression of human dihydropteridine reductase." Lockyer J., Cook R.G., Milstien S., Kaufman S., Woo S.L.C., Ledley F.D. Proc. Natl. Acad. Sci. U.S.A. 84:3329-3333(1987) [PubMed: 3033643] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT THR-51.
[4]	"Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations." Dianzani I., de Sanctis L., Smooker P.M., Gough T.J., Alliaudi C., Brusco A., Spada M., Blau N., Dobos M., Zhang H.-P., Yang N., Ponzone A., Armarego W.L.F., Cotton R.G.H. Hum. Mutat. 12:267-273(1998) [PubMed: 9744478] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT THR-51, VARIANTS PK2 ASP-23; CYS-150; TYR-158 AND ILE-THR-GLY-218 INS.
[5]	"The complete sequence of human dihydropteridine reductase gene containing BAC clone 395N09." Hsiao K.-J., Yen P.-F., Lin C.-H., Liu T.-T., Chiang S.-H., Chen C.-Y., Tsai S.-F. Submitted (DEC-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	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: Cerebellum.
[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: Brain.
[8]	Bienvenut W.V., Heiserich L., Gottlieb E. Submitted (MAR-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-11 AND 128-138, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Colon carcinoma.
[9]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[10]	"The crystallographic structure of a human dihydropteridine reductase NADH binary complex expressed in Escherichia coli by a cDNA constructed from its rat homologue." Su Y., Varughese K.I., Xuong N.H., Bray T.L., Roche D.J., Whiteley J.M. J. Biol. Chem. 268:26836-26841(1993) [PubMed: 8262916] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
[11]	"Molecular basis of dihydropteridine reductase deficiency." Smooker P.M., Cotton R.G.H. Hum. Mutat. 5:279-284(1995) [PubMed: 7627180] [Abstract] Cited for: REVIEW ON VARIANTS.
[12]	"Two new mutations in the dihydropteridine reductase gene in patients with tetrahydrobiopterin deficiency." Dianzani I., Howells D.W., Ponzone A., Saleeba J.A., Smooker P.M., Cotton R.G.H. J. Med. Genet. 30:465-469(1993) [PubMed: 8326489] [Abstract] Cited for: VARIANTS PK2 ASP-23 AND GLY-108.
[13]	"Insertion of an extra codon for threonine is a cause of dihydropteridine reductase deficiency." Howells D.W., Forrest S.M., Dahl H.-H.M., Cotton R.G.H. Am. J. Hum. Genet. 47:279-285(1990) [PubMed: 2116088] [Abstract] Cited for: VARIANT PK2 THR-123 INS.
[14]	"A series of mutations in the dihydropteridine reductase gene resulting in either abnormal RNA splicing or DHPR protein defects." Smooker P.M., Gough T.J., Cotton R.G.H., Alliaudi C., de Sanctis L., Dianzani I. Hum. Mutat. 13:503-504(1999) [PubMed: 10408783] [Abstract] Cited for: VARIANTS PK2 PRO-14 AND VAL-17.
[15]	"Molecular analysis of 16 Turkish families with DHPR deficiency using denaturing gradient gel electrophoresis (DGGE)." Romstad A., Kalkanoglu H.S., Coskun T., Demirkol M., Tokatli A., Dursun A., Baykal T., Oezalp I., Guldberg P., Guettler F. Hum. Genet. 107:546-553(2000) [PubMed: 11153907] [Abstract] Cited for: VARIANTS PK2 ARG-17; ASP-18; ASP-23; ARG-66; ARG-149 AND CYS-150.
+	Additional computationally mapped references.

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Web resources

BIOMDB

Db of mutations causing tetrahydrobiopterin deficiencies

GeneReviews

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Cross-references

Sequence databases

X04882 mRNA. Translation: CAA28571.1.
M16447 mRNA. Translation: AAA52305.1.
AJ006239

AJ006245 Genomic DNA. Translation: CAA06930.1.
AB053170 Genomic DNA. Translation: BAB20429.1.
AK223437 mRNA. Translation: BAD97157.1.
BC000576 mRNA. Translation: AAH00576.1.

IPI

IPI00014439.

PIR

RDHUP. A93655.

RefSeq

NP_000311.2.

UniGene

Hs.75438

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1HDR	X-ray	2.50	A	1-244	[»]

ModBase

Search...

2-D gel databases

REPRODUCTION-2DPAGE

IPI00014439.

Proteomic databases

PeptideAtlas

P09417.

PRIDE

P09417.

Genome annotation databases

Ensembl

ENSG00000151552. Homo sapiens. [Contig view]

GeneID

5860.

KEGG

hsa:5860.

NMPDR

fig|9606.3.peg.23962.

Organism-specific databases

GeneCards

GC04M017097.

H-InvDB

HIX0004120.

HGNC

HGNC:9752. QDPR.

MIM

261630. gene+phenotype.

Orphanet

226. Dihydropteridine reductase deficiency.

PharmGKB

PA34094.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P09417.

HOVERGEN

P09417.

OMA

P09417. ICVAGGW.

Enzyme and pathway databases

BioCyc

MetaCyc:MON-12069.

BRENDA

1.5.1.34. 247.

Reactome

REACT_13. Metabolism of amino acids.

Gene expression databases

ArrayExpress

P09417.

Bgee

P09417.

CleanEx

HS_QDPR.

GermOnline

ENSG00000151552. Homo sapiens.

Family and domain databases

InterPro

IPR002198. DH_sc/Rdtase_SDR.
[Graphical view]

Pfam

PF00106. adh_short. 1 hit.
[Graphical view]

PROSITE

PS00061. ADH_SHORT. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00157. NADH.

NextBio

22758.

SOURCE

Search...

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Entry information

Entry name

DHPR_HUMAN

Accession

Primary (citable) accession number: P09417
Secondary accession number(s): Q53F52, Q9H3M5

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	November 28, 2006
Last modified:	June 16, 2009
This is version 113 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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