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) [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	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.11
Catalytic activity	A nucleoside triphosphate + H2O = a nucleotide + diphosphate. HAMAP-Rule MF_03148
Cofactor	Binds 1 magnesium ion per subunit. Ref.14
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	Inosine triphosphate pyrophosphohydrolase deficiency (ITPAD) [MIM:613850]: A common inherited condition characterized by the abnormal accumulation of inosine triphosphate in erythrocytes. It might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. Note: The disease is caused by mutations affecting the gene represented in this entry. 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.15 Ref.16
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.11 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
Coding sequence diversity	Alternative splicing
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	ITP catabolic process Inferred from electronic annotation. Source: Compara chromosome organization Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from direct assay. Source: HPA
Molecular_function	dITP diphosphatase activity Inferred from electronic annotation. Source: Compara metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW nucleotide binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9BY32-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9BY32-2)

The sequence of this isoform differs from the canonical sequence as follows:
     7-23: Missing.

Note: No experimental confirmation available.

Isoform 3 (identifier: Q9BY32-3)

The sequence of this isoform differs from the canonical sequence as follows:
     23-63: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.9

Chain

2 – 194

193

Inosine triphosphate pyrophosphatase HAMAP-Rule MF_03148

PRO_0000178280

Regions

Region

14 – 19

6

Substrate binding HAMAP-Rule MF_03148

Region

72 – 73

2

Substrate binding HAMAP-Rule MF_03148

Region

149 – 152

4

Substrate binding HAMAP-Rule MF_03148

Region

177 – 178

2

Substrate binding HAMAP-Rule MF_03148

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.9

Natural variations

Alternative sequence

7 – 23

17

Missing in isoform 2.

VSP_042548

Alternative sequence

23 – 63

41

Missing in isoform 3.

VSP_045545

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.15 Ref.16
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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.

.

.

.

.

.

.

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.

.

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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

Beta strand

45 – 47

3

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)
	Isoform 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
	Isoform 2 [UniParc]. Checksum: AAE9E3F8713D476D	FASTA	177	19,603
	10 20 30 40 50 60 MAASLVVQIL GDKFPCTLVA QKIDLPEYQG EPDEISIQKC QEAVRQVQGP VLVEDTCLCF 70 80 90 100 110 120 NALGGLPGPY IKWFLEKLKP EGLHQLLAGF EDKSAYALCT FALSTGDPSQ PVRLFRGRTS 130 140 150 160 170 GRIVAPRGCQ DFGWDPCFQP DGYEQTYAEM PKAEKNAVSH RFRALLELQE YFGSLAA
	Isoform 3 [UniParc]. Checksum: DDC0D289C0158A76	FASTA	153	16,833
	10 20 30 40 50 60 MAASLVGKKI VFVTGNAKKL EEVQGPVLVE DTCLCFNALG GLPGPYIKWF LEKLKPEGLH 70 80 90 100 110 120 QLLAGFEDKS AYALCTFALS TGDPSQPVRL FRGRTSGRIV APRGCQDFGW DPCFQPDGYE 130 140 150 QTYAEMPKAE KNAVSHRFRA LLELQEYFGS LAA

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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), 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] (ISOFORM 1), VARIANT ITPAD THR-32. Tissue: Fetal brain.
[3]	"Molecular cloning of cDNA associated with human lung cancer antigen and study on its functions." Fan M.-Z., Chen Z., Cao Z.-M. Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). 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] (ISOFORMS 1 AND 2).
[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] (ISOFORM 1). 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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	Mural R.J., Istrail S., Sutton 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"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] (ISOFORMS 1 AND 3). Tissue: Lung carcinoma and Neuroblastoma.
[9]	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.
[10]	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.
[11]	"Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase." Burgis N.E., Cunningham R.P. J. Biol. Chem. 282:3531-3538(2007) [PubMed] [Europe PMC] [Abstract] Cited for: SUBSTRATE SPECIFICITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES.
[12]	"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] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.63 ANGSTROMS).
[14]	"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] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS) ALONE AND IN COMPLEX WITH ITP, COFACTOR, MAGNESIUM-BINDING SITES, SUBSTRATE-BINDING SITES.
[15]	"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] [Europe PMC] [Abstract] Cited for: VARIANT ITPAD THR-32.
[16]	"DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency." Cao H., Hegele R.A. J. Hum. Genet. 47:620-622(2002) [PubMed] [Europe PMC] [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.
EF213026 mRNA. Translation: ABO70316.1.
AB062127 mRNA. Translation: BAB93459.1.
AL109976 Genomic DNA. Translation: CAC16798.3.
AL121891, AL109976 Genomic DNA. Translation: CAI19399.1.
AL121891, AL109976 Genomic DNA. Translation: CAM27676.1.
AL109976, AL121891 Genomic DNA. Translation: CAM28311.1.
CH471133 Genomic DNA. Translation: EAX10541.1.
BC010138 mRNA. Translation: AAH10138.1.
BI115811 mRNA. No translation available.

IPI

IPI00018783.
IPI00375446.
IPI00797679.

RefSeq

NP_001254552.1. NM_001267623.1.
NP_258412.1. NM_033453.3.
NP_852470.1. NM_181493.2.

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.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9BY32. 1 interaction.

STRING

9606.ENSP00000369456.

PTM databases

PhosphoSite

Q9BY32.

Polymorphism databases

DMDM

30173120.

Proteomic databases

PaxDb

Q9BY32.

PeptideAtlas

Q9BY32.

PRIDE

Q9BY32.

Protocols and materials databases

DNASU

3704.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000380113; ENSP00000369456; ENSG00000125877.
ENST00000399838; ENSP00000382732; ENSG00000125877.
ENST00000455664; ENSP00000413282; ENSG00000125877.

GeneID

3704.

KEGG

hsa:3704.

UCSC

uc002wid.3. human.

Organism-specific databases

CTD

3704.

GeneCards

GC20P003189.

HGNC

HGNC:6176. ITPA.

HPA

HPA022824.

MIM

147520. gene.
613850. phenotype.

neXtProt

NX_Q9BY32.

Orphanet

284113. Susceptibility to adverse reaction due to mercaptopurine.

PharmGKB

PA29973.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0127.

HOGENOM

HOG000293320.

HOVERGEN

HBG039521.

InParanoid

Q9BY32.

KO

K01519.

OMA

VEDSGFF.

OrthoDB

EOG4THVV4.

PhylomeDB

Q9BY32.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

SABIO-RK

Q9BY32.

Gene expression databases

ArrayExpress

Q9BY32.

Bgee

Q9BY32.

CleanEx

HS_ITPA.

Genevestigator

Q9BY32.

GermOnline

ENSG00000125877. Homo sapiens.

Family and domain databases

HAMAP

MF_03148. HAM1_NTPase.

InterPro

IPR002637. Ham1p-like.
[Graphical view]

PANTHER

PTHR11067. PTHR11067. 1 hit.

Pfam

PF01725. Ham1p_like. 1 hit.
[Graphical view]

TIGRFAMs

TIGR00042. TIGR00042. 1 hit.

ProtoNet

Search...

Other

EvolutionaryTrace

Q9BY32.

GenomeRNAi

3704.

NextBio

14515.

SOURCE

Search...

Entry information

Entry name

ITPA_HUMAN

Accession

Primary (citable) accession number: Q9BY32
Secondary accession number(s): A2A2N2 , A4UIM5, B2BCH7, O14878, Q5JWH4, Q9BYN1, Q9BYX0, Q9H3H8

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 23, 2003
Last sequence update:	April 23, 2003
Last modified:	May 1, 2013
This is version 117 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.