Q9BY32 (ITPA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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):
Non-canonical purine NTP pyrophosphatase
Non-standard purine NTP pyrophosphatase
Nucleoside-triphosphate diphosphatase
Nucleoside-triphosphate pyrophosphatase
Short name=NTPase
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	Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triposphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions. Ref.10
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 (ITPAD) [MIM:613850]. 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. Note=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. Ref.2 Ref.14 Ref.15
Sequence similarities	Belongs to the HAM1 NTPase family.
Biophysicochemical properties	Kinetic parameters: Vmax values are similar for dITP, dHAPTP and dGTP. KM=0.51 mM for ITP Ref.1 Ref.10 KM=0.31 mM for dITP KM=0.57 mM for XTP KM=40.7 µM for dHAPTP KM=933 µM for dGTP Vmax=1520 µmol/min/mg enzyme for ITP Vmax=940 µmol/min/mg enzyme for dITP Vmax=1680 µmol/min/mg enzyme for XTP pH dependence: Optimum pH is 10.

Ontologies

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

Regions

Region

14 – 19

6

Substrate binding

Region

72 – 73

2

Substrate binding

Region

149 – 152

4

Substrate binding

Region

177 – 178

2

Substrate binding

Sites

Metal binding

44

1

Magnesium

Metal binding

72

1

Magnesium By similarity

Binding site

56

1

Substrate

Binding site

172

1

Substrate

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.8

Natural variations

Natural variant

32

1

P → T in ITPAD; complete loss of enzymatic activity at homozygosity; partial loss of activity without ITP accumulation in heterozygous individuals. Ref.2 Ref.14 Ref.15
Corresponds to variant rs1127354 [ dbSNP | Ensembl ].

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 [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 ITPAD 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]	"Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase." Burgis N.E., Cunningham R.P. J. Biol. Chem. 282:3531-3538(2007) [PubMed: 17090528] [Abstract] Cited for: SUBSTRATE SPECIFICITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES.
[11]	"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].
[12]	"Structure of the orthorhombic form of human inosine triphosphate pyrophosphatase." Porta J., Kolar C., Kozmin S.G., Pavlov Y.I., Borgstahl G.E. Acta Crystallogr. F 62:1076-1081(2006) [PubMed: 17077483] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.63 ANGSTROMS).
[13]	"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).
[14]	"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 ITPAD THR-32.
[15]	"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 ITPAD THR-32.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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. NM_033453.2.
NP_852470.1. NM_181493.1.

UniGene

Hs.415299.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ProteinModelPortal

Q9BY32.

SMR

Q9BY32. Positions 1-194.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9BY32. 1 interaction.

STRING

Q9BY32.

PTM databases

PhosphoSite

Q9BY32.

Polymorphism databases

DMDM

30173120.

Proteomic databases

PeptideAtlas

Q9BY32.

PRIDE

Q9BY32.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000380113; ENSP00000369456; ENSG00000125877.

GeneID

3704.

KEGG

hsa:3704.

UCSC

uc002wid.1. human.

Organism-specific databases

CTD

3704.

GeneCards

GC20P003189.

H-InvDB

HIX0015593.

HGNC

HGNC:6176. ITPA.

HPA

HPA022824.

MIM

147520. gene.
613850. phenotype.

neXtProt

NX_Q9BY32.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG05983.

GeneTree

ENSGT00390000015399.

HOVERGEN

HBG039521.

InParanoid

Q9BY32.

OMA

ARQVQGP.

OrthoDB

EOG4THVV4.

PhylomeDB

Q9BY32.

Gene expression databases

ArrayExpress

Q9BY32.

Bgee

Q9BY32.

CleanEx

HS_ITPA.

Genevestigator

Q9BY32.

GermOnline

ENSG00000125877. Homo sapiens.

Family and domain databases

InterPro

IPR002637. Ham1p-like.
[Graphical view]

KO

K01519.

PANTHER

PTHR11067. Ham1p_like. 1 hit.

Pfam

PF01725. Ham1p_like. 1 hit.
[Graphical view]

TIGRFAMs

TIGR00042. TIGR00042. 1 hit.

ProtoNet

Search...

Other

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:	December 14, 2011
This is version 102 of the entry and version 2 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.