Q03393 (PTPS_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
6-pyruvoyl tetrahydrobiopterin synthase
Short name=PTP synthase
Short name=PTPS
EC=4.2.3.12

Gene names

Name:

PTS

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	145 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin.
Catalytic activity	7,8-dihydroneopterin 3'-triphosphate = 6-pyruvoyl-5,6,7,8-tetrahydropterin + triphosphate.
Cofactor	Binds 1 zinc ion per subunit By similarity.
Pathway	Cofactor biosynthesis; tetrahydrobiopterin biosynthesis; tetrahydrobiopterin from 7,8-dihydroneopterin triphosphate: step 1/3.
Subunit structure	Homohexamer formed of two homotrimers in a head to head fashion.
Post-translational modification	Phosphorylation of Ser-19 is required for maximal enzyme activity.
Involvement in disease	Hyperphenylalaninemia, BH4-deficient, A (HPABH4A) [MIM:261640]: An autosomal recessive disorder characterized by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits. Neurological symptoms are unresponsive to the classic phenylalanine-low diet. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.3 Ref.12 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23
Miscellaneous	The active site is at the interface between 2 subunits. The proton acceptor Cys is on one subunit, and the charge relay system is on the other subunit.
Sequence similarities	Belongs to the PTPS family.
Biophysicochemical properties	Kinetic parameters: KM=8.1 µM for 7,8-dihydroneopterin triphosphate Ref.12 Vmax=120 nmol/min/mg enzyme

Ontologies

Keywords
Biological process	Tetrahydrobiopterin biosynthesis
Disease	Disease mutation Phenylketonuria
Ligand	Metal-binding Zinc
Molecular function	Lyase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular amino acid metabolic process Traceable author statement PubMed 3308682. Source: ProtInc central nervous system development Traceable author statement PubMed 3308682. Source: ProtInc nitric oxide metabolic process Traceable author statement. Source: Reactome regulation of nitric-oxide synthase activity Traceable author statement. Source: Reactome tetrahydrobiopterin biosynthetic process Traceable author statement PubMed 3308682. Source: ProtInc
Cellular_component	cytosol Traceable author statement. Source: Reactome mitochondrion Inferred from direct assay. Source: LIFEdb
Molecular_function	6-pyruvoyltetrahydropterin synthase activity Traceable author statement. Source: Reactome metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		3	EBI-712344,EBI-712344

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 145

145

6-pyruvoyl tetrahydrobiopterin synthase

PRO_0000057914

Sites

Active site

43

1

Proton acceptor By similarity

Active site

90

1

Charge relay system By similarity

Active site

134

1

Charge relay system By similarity

Metal binding

24

1

Zinc By similarity

Metal binding

49

1

Zinc By similarity

Metal binding

51

1

Zinc By similarity

Amino acid modifications

Modified residue

19

1

Phosphoserine; by PKG Ref.10 Ref.11 Ref.12

Natural variations

Natural variant

16

1

R → C in HPABH4A; severe decrease in activity; diminishes phosphorylation by PKG. Ref.12 Ref.14 Ref.15

VAR_006816

Natural variant

25

1

R → G in HPABH4A; severe form. Ref.19

VAR_006817

Natural variant

25

1

R → Q in HPABH4A; abolishes activity; no effect on phosphorylation by PKG. Ref.12 Ref.14 Ref.15

VAR_006818

Natural variant

26

1

L → F in HPABH4A. Ref.23

VAR_058265

Natural variant

35

1

E → G in HPABH4A.

VAR_006819

Natural variant

36

1

N → K in HPABH4A.

VAR_006820

Natural variant

47

1

N → D in HPABH4A; transient phenotype; due to partial PTS deficiency; total loss of activity. Ref.21

VAR_008040

Natural variant

52

1

N → S in HPABH4A; severe form; common in Chinese population. Ref.16 Ref.19

VAR_006821

Natural variant

56

1

V → M in HPABH4A; mild form. Ref.19

VAR_006822

Natural variant

57

1

Missing in HPABH4A. Ref.15 Ref.17 Ref.20

VAR_006823

Natural variant

67

1

T → M in HPABH4A. Ref.17 Ref.23

VAR_006824

Natural variant

70

1

V → D in HPABH4A. Ref.19

VAR_006825

Natural variant

87

1

P → L in HPABH4A. Ref.15 Ref.23

VAR_006826

Natural variant

87

1

P → S in HPABH4A; severe form; common in Chinese population. Ref.16 Ref.19

VAR_006827

Natural variant

96

1

D → N in HPABH4A; severe form. Ref.19

VAR_006828

Natural variant

97

1

V → M in HPABH4A. Ref.20

VAR_058266

Natural variant

99

1

Y → C in HPABH4A. Ref.22

VAR_058267

Natural variant

100

1

F → V in HPABH4A.

VAR_006829

Natural variant

106

1

T → M in HPABH4A. Ref.19

VAR_006830

Natural variant

114

1

I → V in HPABH4A. Ref.3 Ref.18

VAR_006831

Natural variant

116

1

D → G in HPABH4A; due to partial PTS deficiency; mild form. Ref.21

VAR_008041

Natural variant

124

1

V → L in HPABH4A. Ref.23

VAR_058268

Natural variant

129

1

K → E in HPABH4A. Ref.17

VAR_006832

Natural variant

136

1

D → G in HPABH4A. Ref.23

VAR_058269

Natural variant

136

1

D → V in HPABH4A. Ref.17 Ref.23

VAR_006833

Experimental info

Mutagenesis

19

1

S → A: Decrease in activity; abolishes phosphorylation by PKG. Ref.12

Sequence conflict

114

1

I → M in AAH18029. Ref.9

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

145

Helix Strand Turn

Details...

Beta strand

11 – 24

14

Beta strand

29 – 31

3

Helix

33 – 40

8

Helix

41 – 44

4

Beta strand

49 – 62

14

Turn

65 – 67

3

Helix

73 – 83

11

Helix

85 – 88

4

Helix

93 – 96

4

Helix

98 – 101

4

Helix

107 – 119

13

Beta strand

127 – 135

9

Beta strand

138 – 142

5

Sequences

	Sequence		Length	Mass (Da)
	Q03393 [UniParc]. Last modified October 1, 1993. Version 1. Checksum: A1CD0DC2F83187E0	FASTA	145	16,386
	10 20 30 40 50 60 MSTEGGGRRC QAQVSRRISF SASHRLYSKF LSDEENLKLF GKCNNPNGHG HNYKVVVTVH 70 80 90 100 110 120 GEIDPATGMV MNLADLKKYM EEAIMQPLDH KNLDMDVPYF ADVVSTTENV AVYIWDNLQK 130 140 VLPVGVLYKV KVYETDNNIV VYKGE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human 6-pyruvoyltetrahydropterin synthase: cDNA cloning and heterologous expression of the recombinant enzyme." Thoeny B., Leimbacher W., Buergisser D., Heizmann C.W. Biochem. Biophys. Res. Commun. 189:1437-1443(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[2]	"cDNA cloning, expression in Escherichia coli and purification of human 6-pyruvoyl-tetrahydropterin synthase." Ashida A., Hatakeyama K., Kagamiyama H. Biochem. Biophys. Res. Commun. 195:1386-1393(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"A missense mutation (A to G) of 6-pyruvoyltetrahydropterin synthase in tetrahydrobiopterin-deficient form of hyperphenylalaninemia." Ashida A., Owada M., Hatakeyama K. Genomics 24:408-410(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT HPABH4A VAL-114.
[4]	"Chromosomal localization, genomic structure and characterization of the human gene and a retropseudogene for 6-pyruvoyltetrahydropterin synthase." Kluge C., Brecevic L., Heizmann C.W., Blau N., Thoeny B. Eur. J. Biochem. 240:477-484(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Genomic structure of 6-pyruvoyl-tetrahydropterin synthase gene and a T/C polymorphism detected in Chinese." Liu T.T., Lu S.F., Hsiao K.J. J. Biomed. Lab. Sci. 10:39-47(1998) Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"Isolation and sequencing of human 6-pyruvoyl-tetrahydropterin synthase gene containing BAC clone 321H15." Hsiao K.-J., Liu T.-T., Chang Y.-H., Chiu Y.-H., Chiang S.-H., Chang H.-M., Chen C.-Y., Tsai S.-F. Submitted (MAY-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	NHLBI resequencing and genotyping service (RS&G) Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain and Pancreas.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"Serine 19 of human 6-pyruvoyltetrahydropterin synthase is phosphorylated by cGMP protein kinase II." Scherer-Oppliger T., Leimbacher W., Blau N., Thoeny B. J. Biol. Chem. 274:31341-31348(1999) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS HPABH4A CYS-16 AND GLN-25, KINETIC PARAMETERS, PHOSPHORYLATION AT SER-19, MUTAGENESIS OF SER-19.
[13]	"Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes." Thoeny B., Blau N. Hum. Mutat. 10:11-20(1997) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON VARIANTS.
[14]	"Hyperphenylalaninemia due to defects in tetrahydrobiopterin metabolism: molecular characterization of mutations in 6-pyruvoyl-tetrahydropterin synthase." Thoeny B., Leimbacher W., Blau N., Harvie A., Heizmann C.W. Am. J. Hum. Genet. 54:782-792(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HPABH4A CYS-16 AND GLN-25.
[15]	"Structural and functional consequences of mutations in 6-pyruvoyltetrahydropterin synthase causing hyperphenylalaninemia in humans. Phosphorylation is a requirement for in vivo activity." Oppliger T., Thoeny B., Nar H., Buergisser D., Huber R., Heizmann C.W., Blau N. J. Biol. Chem. 270:29498-29506(1995) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS HPABH4A CYS-16; GLN-25; VAL-57 DEL AND LEU-87.
[16]	"Identification of a common 6-pyruvoyl-tetrahydropterin synthase mutation at codon 87 in Chinese phenylketonuria caused by tetrahydrobiopterin synthesis deficiency." Liu T.T., Hsiao K.J. Hum. Genet. 98:313-316(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HPABH4A SER-52 AND SER-87.
[17]	"Identification of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency in four Italian families." Oppliger T., Thoeny B., Kluge C., Matasovic A., Heizmann C.W., Ponzone A., Spada M., Blau N. Hum. Mutat. 10:25-35(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HPABH4A VAL-57 DEL; MET-67; GLU-129 AND VAL-136.
[18]	"6-pyruvoyl-tetrahydropterin synthase deficiency with generalized dystonia and diurnal fluctuation of symptoms: a clinical and molecular study." Hanihara T., Inoue K., Kawanishi C., Sugiyama N., Miyakawa T., Onishi H., Yamada Y., Osaka H., Kosaka K., Iwabuchi K., Owada M. Mov. Disord. 12:408-411(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HPABH4A VAL-114.
[19]	"Mutation analysis of the 6-pyruvoyl-tetrahydropterin synthase gene in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency." Liu T.-T., Hsiao K.-J., Lu S.-F., Wu S.-J., Wu K.-F., Chiang S.-H., Liu X.-Q., Chen R.-G., Yu W.-M. Hum. Mutat. 11:76-83(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HPABH4A GLY-25; SER-52; MET-56; ASP-70; SER-87; ASN-96 AND MET-106.
[20]	"Single-step mutation scanning of the 6-pyruvoyltetrahydropterin synthase gene in patients with hyperphenylalaninemia." Romstad A., Guldberg P., Blau N., Guettler F. Clin. Chem. 45:2102-2108(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HPABH4A VAL-57 DEL AND MET-97.
[21]	"Dominant negative allele (N47D) in a compound heterozygote for a variant of 6-pyruvoyltetrahydropterin synthase deficiency causing transient hyperphenylalaninemia." Scherer-Oppliger T., Matasovic A., Laufs S., Levy H.L., Quackenbush E.J., Blau N., Thoeny B. Hum. Mutat. 13:286-289(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HPABH4A ASP-47 AND GLY-116.
[22]	"Isolated central form of tetrahydrobiopterin deficiency associated with hemizygosity on chromosome 11q and a mutant allele of PTPS." Blau N., Scherer-Oppliger T., Baumer A., Riegel M., Matasovic A., Schinzel A., Jaeken J., Thoeny B. Hum. Mutat. 16:54-60(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HPABH4A CYS-99.
[23]	"Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency." Dudesek A., Roeschinger W., Muntau A.C., Seidel J., Leupold D., Thoeny B., Blau N. Eur. J. Pediatr. 160:267-276(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HPABH4A PHE-26; MET-67; LEU-87; LEU-124; GLY-136 AND VAL-136.
+	Additional computationally mapped references.

Web resources

BIOMDB

Db of mutations causing tetrahydrobiopterin deficiencies

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M97655 mRNA. Translation: AAA51541.1.
D17400 mRNA. Translation: BAA04224.1.
D25234 Genomic DNA. Translation: BAA04959.1.
L76259 Genomic DNA. Translation: AAB64229.1.
U63383 , U63380, U63381, U63382 Genomic DNA. Translation: AAC16970.1.
AB042297 Genomic DNA. Translation: BAA95486.1.
EF445018 Genomic DNA. Translation: ACA06065.1.
CH471065 Genomic DNA. Translation: EAW67195.1.
BC009686 mRNA. Translation: AAH09686.1.
BC018029 mRNA. Translation: AAH18029.1.

IPI

IPI00010339.

PIR

JC1405.

RefSeq

NP_000308.1. NM_000317.2.

UniGene

Hs.503860.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3I2B	X-ray	2.30	A/B/C/D/E/F/G/H/I/J/K/L	7-145	[»]

ProteinModelPortal

Q03393.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q03393. 3 interactions.

MINT

MINT-1419639.

STRING

9606.ENSP00000280362.

PTM databases

PhosphoSite

Q03393.

Polymorphism databases

DMDM

417553.

Proteomic databases

PaxDb

Q03393.

PRIDE

Q03393.

Protocols and materials databases

DNASU

5805.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000280362; ENSP00000280362; ENSG00000150787.

GeneID

5805.

KEGG

hsa:5805.

UCSC

uc001pnj.4. human.

Organism-specific databases

CTD

5805.

GeneCards

GC11P112097.

HGNC

HGNC:9689. PTS.

HPA

HPA001481.

MIM

261640. phenotype.
612719. gene.

neXtProt

NX_Q03393.

Orphanet

13. 6-pyruvoyl-tetrahydropterin synthase deficiency.

PharmGKB

PA34032.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0720.

HOGENOM

HOG000225069.

HOVERGEN

HBG004358.

InParanoid

Q03393.

KO

K01737.

OMA

EVKIHET.

OrthoDB

EOG4V1722.

PhylomeDB

Q03393.

Enzyme and pathway databases

BioCyc

MetaCyc:HS07692-MONOMER.

BRENDA

4.2.3.12. 2681.

Reactome

REACT_111217. Metabolism.

SABIO-RK

Q03393.

UniPathway

UPA00849; UER00819.

Gene expression databases

ArrayExpress

Q03393.

Bgee

Q03393.

CleanEx

HS_PTS.

Genevestigator

Q03393.

GermOnline

ENSG00000150787. Homo sapiens.

Family and domain databases

InterPro

IPR007115. 6-PTP_synth/QueD.
IPR022470. PTPS_Cys_AS.
IPR022469. PTPS_His_AS.
[Graphical view]

PANTHER

PTHR12589. PTHR12589. 1 hit.

Pfam

PF01242. PTPS. 1 hit.
[Graphical view]

PIRSF

PIRSF006113. PTP_synth. 1 hit.

TIGRFAMs

TIGR00039. 6PTHBS. 1 hit.

PROSITE

PS00987. PTPS_1. 1 hit.
PS00988. PTPS_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q03393.

GenomeRNAi

5805.

NextBio

22628.

SOURCE

Search...

Entry information

Entry name

PTPS_HUMAN

Accession

Primary (citable) accession number: Q03393
Secondary accession number(s): B0YJ87, Q8WVG8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1993
Last sequence update:	October 1, 1993
Last modified:	May 1, 2013
This is version 139 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.