Reviewed, UniProtKB/Swiss-Prot Q9BY32 (ITPA_HUMAN)

Names and origin

Protein names

Recommended name:
    Inosine triphosphate pyrophosphatase
      Short name=ITPase
      Short name=Inosine triphosphatase
    EC=3.6.1.19
Alternative name(s):
    Putative oncogene protein hlc14-06-p

Gene names

Name:	ITPA
Synonyms:	C20orf37
ORF Names:	My049, OK/SW-cl.9

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	194 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	Hydrolyzes ITP and dITP to their respective monophosphate derivatives. Xanthosine 5'-triphosphate (XTP) is also a potential substrate. May be the major enzyme responsible for regulating ITP concentration in cells.
Catalytic activity	A nucleoside triphosphate + H2O = a nucleotide + diphosphate.
Cofactor	Binds 1 magnesium ion per subunit.
Subunit structure	Homodimer. Ref.1
Subcellular location	Cytoplasm. Ref.1
Tissue specificity	Ubiquitous. Highly expressed in heart, liver, sex glands, thyroid and adrenal gland.
Involvement in disease	Defects in ITPA are the cause of inosine triphosphate pyrophosphohydrolase deficiency (ITPA deficiency) [MIM:147520]. It is a common inherited trait characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes and also leukocytes and fibroblasts. The pathological consequences of ITPA deficiency, if any, are unknown. However, it might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme.
Sequence similarities	Belongs to the HAM1 NTPase family.
biophysicochemical properties	Kinetic parameters: KM=0.51 mM for ITP KM=0.31 mM for dITP KM=0.57 mM for xanthosine 5'-triphosphate

Ontologies

Keywords
Biological process	Nucleotide metabolism
Cellular component	Cytoplasm
Disease	Disease mutation
Ligand	Magnesium Metal-binding
Molecular function	Hydrolase
PTM	Acetylation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	nucleotide metabolic process Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW nucleoside-triphosphate diphosphatase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.8

Chain

2 – 194

193

Inosine triphosphate pyrophosphatase

PRO_0000178280

Sites

Metal binding

44

1

Magnesium

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.8

Natural variations

Natural variant

32

1

P → T in ITPA deficiency; complete loss of enzymatic activity at homozygosity; partial loss of activity without ITP accumulation in heterozygous individuals. dbSNP rs1127354.

VAR_015576

Experimental info

Sequence conflict

33

1

C → R in AAK21848. Ref.1

Sequence conflict

41

1

D → G in AAG43165. Ref.2

Secondary structure

1

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194

Helix Strand Turn

Details...

Helix

2 – 5

4

Beta strand

9 – 13

5

Helix

17 – 27

11

Beta strand

33 – 38

6

Helix

49 – 64

16

Beta strand

68 – 77

10

Helix

78 – 80

3

Helix

88 – 102

15

Turn

103 – 106

4

Beta strand

111 – 121

11

Beta strand

130 – 140

11

Helix

152 – 154

3

Beta strand

155 – 157

3

Turn

164 – 166

3

Helix

169 – 175

7

Helix

177 – 189

13

Sequences

	Sequence		Length	Mass (Da)
	Q9BY32-1 [UniParc]. Last modified April 23, 2003. Version 2. Checksum: F0EC6A523722DF05	FASTA	194	21,446
	10 20 30 40 50 60 MAASLVGKKI VFVTGNAKKL EEVVQILGDK FPCTLVAQKI DLPEYQGEPD EISIQKCQEA 70 80 90 100 110 120 VRQVQGPVLV EDTCLCFNAL GGLPGPYIKW FLEKLKPEGL HQLLAGFEDK SAYALCTFAL 130 140 150 160 170 180 STGDPSQPVR LFRGRTSGRI VAPRGCQDFG WDPCFQPDGY EQTYAEMPKA EKNAVSHRFR 190 ALLELQEYFG SLAA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the ITPA gene." Lin S., McLennan A.G., Ying K., Wang Z., Gu S., Jin H., Wu C., Lu W., Yuan Y., Tang R., Xie Y., Mao Y. J. Biol. Chem. 276:18695-18701(2001) [PubMed: 11278832] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBUNIT, SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL PROPERTIES. Tissue: Fetal brain.
[2]	Mao Y.M., Xie Y., Zheng Z.H. Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ITPA DEFICIENCY THR-32. Tissue: Fetal brain.
[3]	"Molecular cloning of cDNA associated with human lung cancer antigen and study on its fuctions." Fan M.-Z., Chen Z., Cao Z.-M. Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lung carcinoma.
[4]	Danaei Y., Behmanesh M., Sadeghi Zadeh M. Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"Identification of immuno-peptidmics that are recognized by tumor-reactive CTL generated from TIL of colon cancer patients." Shichijo S., Itoh K. Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Colon adenocarcinoma.
[6]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] 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: Neuroblastoma.
[8]	Bienvenut W.V., Waridel P., Quadroni M. Submitted (MAR-2009) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-9; 40-56; 95-110 AND 181-194, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[9]	Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 10-56 AND 95-130, MASS SPECTROMETRY. Tissue: Brain, Cajal-Retzius cell and Fetal brain cortex.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"Crystal structure of human inosine triphosphatase. Substrate binding and implication of the inosine triphosphatase deficiency mutation P32T." Stenmark P., Kursula P., Flodin S., Graslund S., Landry R., Nordlund P., Schueler H. J. Biol. Chem. 282:3182-3187(2007) [PubMed: 17138556] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS).
[12]	"Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency." Sumi S., Marinaki A.M., Arenas M., Fairbanks L., Shobowale-Bakre M., Rees D.C., Thein S.L., Ansari A., Sanderson J., De Abreu R.A., Simmonds H.A., Duley J.A. Hum. Genet. 111:360-367(2002) [PubMed: 12384777] [Abstract] Cited for: VARIANT ITPA DEFICIENCY THR-32.
[13]	"DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency." Cao H., Hegele R.A. J. Hum. Genet. 47:620-622(2002) [PubMed: 12436200] [Abstract] Cited for: VARIANT ITPA DEFICIENCY THR-32.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF219116 mRNA. Translation: AAK21848.1.
AF063607 mRNA. Translation: AAG43165.1.
AF026816 mRNA. Translation: AAB82608.2.
EF199841 mRNA. Translation: ABP01354.1.
AB062127 mRNA. Translation: BAB93459.1.
AL109976 Genomic DNA. Translation: CAC16798.3.
AL121891, AL109976 Genomic DNA. Translation: CAI19399.1.
BC010138 mRNA. Translation: AAH10138.1.

IPI

IPI00018783.

RefSeq

NP_258412.1.
NP_852470.1.

UniGene

Hs.415299

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CAR	X-ray	1.09	A/B	1-194	[»]
2I5D	X-ray	1.63	A	1-194	[»]
2J4E	X-ray	2.80	A/B/C/D/E/F/G/H	1-194	[»]

ModBase

Search...

PTM databases

PhosphoSite

Q9BY32.

Proteomic databases

PeptideAtlas

Q9BY32.

PRIDE

Q9BY32.

Genome annotation databases

Ensembl

ENSG00000125877. Homo sapiens. [Contig view]

GeneID

3704.

KEGG

hsa:3704.

Organism-specific databases

GeneCards

GC20P003138.

HGNC

HGNC:6176. ITPA.

MIM

147520. gene+phenotype.

PharmGKB

PA29973.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q9BY32.

HOVERGEN

Q9BY32.

OMA

Q9BY32. RQVQGPV.

Enzyme and pathway databases

BRENDA

3.6.1.19. 247.

Gene expression databases

ArrayExpress

Q9BY32.

Bgee

Q9BY32.

CleanEx

HS_ITPA.

GermOnline

ENSG00000125877. Homo sapiens.

Family and domain databases

InterPro

IPR002637. Ham1p-like.
[Graphical view]

PANTHER

PTHR11067. Ham1p_like. 1 hit.

Pfam

PF01725. Ham1p_like. 1 hit.
[Graphical view]

TIGRFAMs

TIGR00042. Ham1p_like. 1 hit.

ProtoNet

Search...

Other Resources

NextBio

14515.

SOURCE

Search...

Entry information

Entry name

ITPA_HUMAN

Accession

Primary (citable) accession number: Q9BY32
Secondary accession number(s): A4UIM5 , O14878, Q5JWH4, Q9BYN1, Q9BYX0, Q9H3H8

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 23, 2003
Last sequence update:	April 23, 2003
Last modified:	June 16, 2009
This is version 76 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)