Reviewed, UniProtKB/Swiss-Prot P09417 (DHPR_HUMAN)

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) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

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.

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 BH4-deficient hyperphenylalaninemia type C (HPABH4C) [MIM:261630]; also called dihydropteridine reductase deficiency (DHPR deficiency) or hyperphenylalaninemia tetrahydrobiopterin-deficient due to DHPR deficiency or quinoid dihydropteridine reductase deficiency (QDPR deficiency). HPABH4C 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. HPABH4C is lethal if untreated. Ref.4 Ref.15 Ref.16 Ref.17 Ref.18
Sequence similarities	Belongs to the short-chain dehydrogenases/reductases (SDR) family.

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 Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	cellular amino acid metabolic process Ref.3 Traceable author statement. Source: ProtInc 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...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.10

Chain

2 – 244

243

Dihydropteridine reductase

PRO_0000054636

Regions

Nucleotide binding

14 – 38

25

NADP

Sites

Active site

150

1

Proton acceptor

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.10 Ref.12

Natural variations

Natural variant

14

1

L → P in HPABH4C; severe. Ref.17

VAR_008121

Natural variant

17

1

G → R in HPABH4C; severe. Ref.18

VAR_021767

Natural variant

17

1

G → V in HPABH4C; severe. Ref.17

VAR_008122

Natural variant

18

1

G → D in HPABH4C; severe. Ref.18

VAR_021768

Natural variant

23

1

G → D in HPABH4C; severe. Ref.4 Ref.15 Ref.18

VAR_006960

Natural variant

36

1

W → R in HPABH4C.

VAR_006961

Natural variant

51

1

S → T

VAR_013027

Natural variant

66

1

Q → R in HPABH4C; severe. Ref.18

VAR_021769

Natural variant

74

1

L → P in HPABH4C.

VAR_006962

Natural variant

108

1

W → G in HPABH4C. Ref.15

VAR_006963

Natural variant

123

1

T → TT in HPABH4C. Ref.16

VAR_006964

Natural variant

145

1

P → L in HPABH4C.

VAR_006965

Natural variant

149

1

G → R in HPABH4C. Ref.18

VAR_021770

Natural variant

150

1

Y → C in HPABH4C; mild. Ref.4 Ref.18

VAR_006966

Natural variant

151

1

G → S in HPABH4C; mild.

VAR_006967

Natural variant

158

1

H → Y in HPABH4C; severe. Ref.4

VAR_006968

Natural variant

170

1

G → S in HPABH4C.

VAR_006969

Natural variant

212

1

F → C in HPABH4C; mild.

VAR_006970

Natural variant

218

1

G → GITG in HPABH4C; mild.

VAR_006971

Secondary structure

1

.

.

.

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.

.

.

.

.

.

.

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244

Helix Strand Turn

Details...

Beta strand

11 – 16

6

Turn

17 – 19

3

Helix

21 – 32

12

Beta strand

36 – 43

8

Beta strand

48 – 53

6

Helix

60 – 75

16

Beta strand

80 – 85

6

Helix

100 – 110

11

Helix

112 – 125

14

Beta strand

126 – 135

10

Helix

138 – 141

4

Helix

148 – 165

18

Beta strand

176 – 181

6

Helix

188 – 191

4

Helix

199 – 201

3

Helix

205 – 216

12

Turn

217 – 220

4

Beta strand

227 – 233

7

Beta strand

236 – 242

7

Sequences

	Sequence		Length	Mass (Da)
	P09417-1 [UniParc]. Last modified November 28, 2006. Version 2. Checksum: 0852F9F0CA38AB1C	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

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 HPABH4C 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]	"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: Brain.
[7]	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.
[8]	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 (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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.
[10]	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.
[11]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[12]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY.
[13]	"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).
[14]	"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.
[15]	"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 HPABH4C ASP-23 AND GLY-108.
[16]	"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 HPABH4C THR-123 INS.
[17]	"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 HPABH4C PRO-14 AND VAL-17.
[18]	"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 HPABH4C ARG-17; ASP-18; ASP-23; ARG-66; ARG-149 AND CYS-150.
+	Additional computationally mapped references.

Web resources

BIOMDB

Db of mutations causing tetrahydrobiopterin deficiencies

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X04882 mRNA. Translation: CAA28571.1.
M16447 mRNA. Translation: AAA52305.1.
AJ006239 , AJ006240, AJ006241, AJ006242, AJ006243, AJ006244, AJ006245 Genomic DNA. Translation: CAA06930.1.
AB053170 Genomic DNA. Translation: BAB20429.1.
AK223437 mRNA. Translation: BAD97157.1.
AK289773 mRNA. Translation: BAF82462.1.
CH471069 Genomic DNA. Translation: EAW92777.1.
BC000576 mRNA. Translation: AAH00576.1.

IPI

IPI00014439.

PIR

RDHUP. A93655.

RefSeq

NP_000311.2.

UniGene

Hs.75438

3D structure databases

PDBe
RCSB PDB
PDBj

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

ModBase

Search...

Protein-protein interaction databases

STRING

P09417.

2-D gel databases

REPRODUCTION-2DPAGE

IPI00014439.

Proteomic databases

PeptideAtlas

P09417.

PRIDE

P09417.

Genome annotation databases

Ensembl

ENST00000281243; ENSP00000281243; ENSG00000151552; Homo sapiens. [Genome view]

GeneID

5860.

KEGG

hsa:5860.

NMPDR

fig|9606.3.peg.23962.

Organism-specific databases

CTD

5860.

GeneCards

GC04M017097.

H-InvDB

HIX0004120.

HGNC

HGNC:9752. QDPR.

MIM

261630. phenotype.
612676. gene.

Orphanet

226. Dihydropteridine reductase deficiency.

PharmGKB

PA34094.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG18413.

HOGENOM

HBG380758.

HOVERGEN

P09417.

InParanoid

P09417.

OMA

ICVAGGW.

OrthoDB

EOG9R26D4.

PhylomeDB

P09417.

Enzyme and pathway databases

BioCyc

MetaCyc:MONOMER-12069.

BRENDA

1.5.1.34. 247.

Reactome

REACT_13. Metabolism of amino acids.

Gene expression databases

ArrayExpress

P09417.

Bgee

P09417.

CleanEx

HS_QDPR.

Genevestigator

P09417.

GermOnline

ENSG00000151552. Homo sapiens.

Family and domain databases

InterPro

IPR002198. DH_sc/Rdtase_SDR.
IPR016040. NAD(P)-bd_dom.
IPR020904. Sc_DH/Rdtase_CS.
[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...

Entry information

Entry name

DHPR_HUMAN

Accession

Primary (citable) accession number: P09417
Secondary accession number(s): A8K158, Q53F52, Q9H3M5

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	November 28, 2006
Last modified:	January 19, 2010
This is version 122 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.