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Information on EC 3.6.1.66 - XTP/dITP diphosphatase
for references in articles please use BRENDA:EC3.6.1.66
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EC Tree 3 Hydrolases
3.6 Acting on acid anhydrides
3.6.1 In phosphorus-containing anhydrides
3.6.1.66 XTP/dITP diphosphatase
IUBMB Comments
The enzymes from the bacterium Escherichia coli and the archaea Methanococcus jannaschii and Archaeoglobus fulgidus are highly specific for XTP, dITP and ITP. The activity is dependent on divalent cations, Mg2+ is preferred.
The enzyme appears in viruses and cellular organisms
showSynonyms
mj0226, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
dITP/XTP pyrophosphatase
hypoxanthine/xanthine dNTP pyrophosphatase
inosine triphosphatase
inosine triphosphate pyrophosphatase
ITPA
ITPase
ITPase Ham1
Mj0226
PH1917
TbITPA
TM0159
viral inosine triphosphatase
inosine triphosphate pyrophosphatase
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
dITP + H2O = dIMP + diphosphate
-
-
-
-
XTP + H2O = XMP + diphosphate
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
KEGG
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SYSTEMATIC NAME
IUBMB Comments
XTP/dITP diphosphohydrolase (diphosphate-forming)
The enzymes from the bacterium Escherichia coli and the archaea Methanococcus jannaschii and Archaeoglobus fulgidus are highly specific for XTP, dITP and ITP. The activity is dependent on divalent cations, Mg2+ is preferred.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
dGTP + H2O
dGMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: i.e. 2'-deoxyinosine 5'-triphosphate
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: i.e. 2'-deoxyinosine 5'-triphosphate
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: -
Products: -
Products: -
?
dITP + H2O
dTDP + phosphate
Substrates: ITP and dITP are slightly preferred over XTP
Products: -
Products: -
?
dITP + H2O
dTDP + phosphate
Substrates: ITP and dITP are slightly preferred over XTP
Products: -
Products: -
?
ITP + H2O
IDP + phosphate
Substrates: ITP and dITP are slightly preferred over XTP
Products: -
Products: -
?
ITP + H2O
IDP + phosphate
Substrates: ITP and dITP are slightly preferred over XTP
Products: -
Products: -
?
ITP + H2O
IMP + diphosphate
Substrates: -
Products: -
Products: -
?
ITP + H2O
IMP + diphosphate
Substrates: catalytic efficiency (kcat/Km) is about 60% compared to the catalytic efficiency of XTP
Products: -
Products: -
?
ITP + H2O
IMP + diphosphate
Substrates: -
Products: -
Products: -
?
ITP + H2O
IMP + diphosphate
Substrates: catalytic efficiency (kcat/Km) is about 60% compared to the catalytic efficiency of XTP
Products: -
Products: -
?
ITP + H2O
IMP + diphosphate
Substrates: -
Products: -
Products: -
?
ribavirin triphosphate + H2O
ribavirin 5'-monophosphate + diphosphate
Substrates: -
Products: -
Products: -
?
ribavirin triphosphate + H2O
ribavirin 5'-monophosphate + diphosphate
Trypanosoma brucei brucei 4GUTat10.1
Substrates: -
Products: -
Products: -
?
ribavirin triphosphate + H2O
ribavirin 5'-monophosphate + diphosphate
Substrates: -
Products: -
Products: -
?
XTP + H2O
XDP + phosphate
Substrates: ITP and dITP are slightly preferred over XTP
Products: -
Products: -
?
XTP + H2O
XDP + phosphate
Substrates: ITP and dITP are slightly preferred over XTP
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: -
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: -
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: -
Products: -
Products: -
?
additional information
?
-
Substrates: ITPA seems mainly involved with ITP and IDP and somewhat with dITP dephosphorylation in vivo
Products: -
Products: -
-
additional information
?
-
Substrates: reaction rate is less than 1% compared to dITP or XTP with the following substrates: dGTP, dATP, dCTP, dTTP, dUTP
Products: -
Products: -
?
additional information
?
-
-
Substrates: reaction rate is less than 1% compared to dITP or XTP with the following substrates: dGTP, dATP, dCTP, dTTP, dUTP
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme shows weak activity toward canonical nucleotides, with highest activity towards deoxyguanosine triphosphate (dGTP) and guanosine triphosphate (GTP)
Products: -
Products: -
-
additional information
?
-
-
Substrates: reaction rate is less than 2% compared to dITP or XTP with the following substrates: dGTP, dATP, dCTP, dTTP, dUTP
Products: -
Products: -
?
additional information
?
-
Substrates: catalytic efficiency (kcat/Km) is less than 1% compared to dITP or XTP with the following substrates: dGTP, GTP, dATP, dCTP, dTTP, dUTP, 8-oxo-dGTP. Neither endonuclease nor 3'-exonuclease activities were detected in this protein
Products: -
Products: -
?
additional information
?
-
-
Substrates: catalytic efficiency (kcat/Km) is less than 1% compared to dITP or XTP with the following substrates: dGTP, GTP, dATP, dCTP, dTTP, dUTP, 8-oxo-dGTP. Neither endonuclease nor 3'-exonuclease activities were detected in this protein
Products: -
Products: -
?
additional information
?
-
Substrates: catalytic efficiency (kcat/Km) for GTP, dGTP, ATP, CTP or TTP is less than 1% compared to the catalytic efficiency of XTP
Products: -
Products: -
?
additional information
?
-
-
Substrates: catalytic efficiency (kcat/Km) for GTP, dGTP, ATP, CTP or TTP is less than 1% compared to the catalytic efficiency of XTP
Products: -
Products: -
?
additional information
?
-
Substrates: catalytic efficiency (kcat/Km) for GTP, dGTP, ATP, CTP or TTP is less than 1% compared to the catalytic efficiency of XTP
Products: -
Products: -
?
additional information
?
-
Substrates: recombinant TbITPA efficiently hydrolyzes (deoxy)ITP and XTP nucleotides into their respective monophosphate form. No activity is detected with the canonical nucleotides ATP, GTP, dATP and dGTP
Products: -
Products: -
-
additional information
?
-
Trypanosoma brucei brucei 4GUTat10.1
Substrates: recombinant TbITPA efficiently hydrolyzes (deoxy)ITP and XTP nucleotides into their respective monophosphate form. No activity is detected with the canonical nucleotides ATP, GTP, dATP and dGTP
Products: -
Products: -
-
additional information
?
-
Substrates: recombinant TbITPA efficiently hydrolyzes (deoxy)ITP and XTP nucleotides into their respective monophosphate form. No activity is detected with the canonical nucleotides ATP, GTP, dATP and dGTP
Products: -
Products: -
-
additional information
?
-
-
Substrates: the enzyme shows weak activity toward canonical nucleotides, with highest activity towards deoxyguanosine triphosphate (dGTP) and guanosine triphosphate (GTP)
Products: -
Products: -
-
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
Substrates: ITPA seems mainly involved with ITP and IDP and somewhat with dITP dephosphorylation in vivo
Products: -
Products: -
-
dGTP + H2O
dGMP + diphosphate
-
Substrates: -
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
dITP + H2O
dIMP + diphosphate
Substrates: -
Products: -
Products: -
?
ITP + H2O
IMP + diphosphate
Substrates: -
Products: -
Products: -
?
ITP + H2O
IMP + diphosphate
Substrates: -
Products: -
Products: -
?
ribavirin triphosphate + H2O
ribavirin 5'-monophosphate + diphosphate
Substrates: -
Products: -
Products: -
?
ribavirin triphosphate + H2O
ribavirin 5'-monophosphate + diphosphate
Trypanosoma brucei brucei 4GUTat10.1
Substrates: -
Products: -
Products: -
?
ribavirin triphosphate + H2O
ribavirin 5'-monophosphate + diphosphate
Substrates: -
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
Products: -
Products: -
?
XTP + H2O
XMP + diphosphate
Substrates: -
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
Mn2+
NTPase activities are most efficient in the presence of either Mg2+ or Mn2+ at 80°C
Ni2+
the enzyme requires a divalent cation. Mg2+ is required for optimal activity, with Mn2+, Zn2+ and Ni2+ supporting less than 50% of the maximum rate
Zn2+
the enzyme requires a divalent cation. Mg2+ is required for optimal activity, with Mn2+, Zn2+ and Ni2+ supporting less than 50% of the maximum rate
Mg2+
the enzyme requires a divalent cation. Mg2+ is required for optimal activity, with Mn2+, Zn2+ and Ni2+ supporting less than 50% of the maximum rate
Mg2+
NTPase activities are most efficient in the presence of either Mg2+ or Mn2+ at 80°C
Mg2+
absolute requirement for Mg2+. At 10 mM Mg2+ concentration, the enzyme reaches a plateau of optimum activity. Other divalent and monovalent cations barely support the catalytic activity of TM0159. Samples containing up to 100 mM Mn2+, Zn2+, Co2+, Cu2+, Na+, K+ or Li+ show less than 10% of the activity measured at 10 mM Mg2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
inosine triphosphate
-
ITP, may act as a competitive inhibitor for activity towards canonical nucleotide substrates in vivo
inosine triphosphate
-
ITP, may act as a competitive inhibitor for activity towards canonical nucleotide substrates in vivo
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.075
ribavirin triphosphate
pH 7.5, 25°C, recombinant enzyme
additional information
additional information
Michaelis-Menten enzyme kinetics of wild-type and mutant enzymes, overview
-
0.0017
dITP
pH and temperature not specified in the publication, recombinant enzyme
0.0071
ITP
pH and temperature not specified in the publication, recombinant enzyme
0.0117
ITP
pH not specified in the publication, 37°C, recombinant wild-type enzyme
0.0184
ITP
pH not specified in the publication, 37°C, recombinant mutant R178C
0.115
ITP
pH not specified in the publication, 37°C, recombinant mutant R178A
0.116
ITP
pH not specified in the publication, 37°C, recombinant mutant R178S
0.216
ITP
pH not specified in the publication, 37°C, recombinant mutant R178K
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.5
dITP
pH and temperature not specified in the publication, recombinant enzyme
0.022
ITP
pH not specified in the publication, 37°C, recombinant mutant R178A
0.038
ITP
pH not specified in the publication, 37°C, recombinant mutant R178C
0.072
ITP
pH not specified in the publication, 37°C, recombinant mutant R178S
1.9
ITP
pH and temperature not specified in the publication, recombinant enzyme
3.3
ITP
pH not specified in the publication, 37°C, recombinant mutant R178K
4.7
ITP
pH not specified in the publication, 37°C, recombinant wild-type enzyme
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1333.3
ribavirin triphosphate
pH 7.5, 25°C, recombinant enzyme
882.4
dITP
pH and temperature not specified in the publication, recombinant enzyme
6363.6
dITP
pH 7.5, 25°C, recombinant enzyme, calculated by BRENDA
0.2
ITP
pH not specified in the publication, 37°C, recombinant mutant R178A
0.62
ITP
pH not specified in the publication, 37°C, recombinant mutant R178S
2.1
ITP
pH not specified in the publication, 37°C, recombinant mutant R178C
15.2
ITP
pH not specified in the publication, 37°C, recombinant mutant R178K
267.6
ITP
pH and temperature not specified in the publication, recombinant enzyme
401
ITP
pH not specified in the publication, 37°C, recombinant wild-type enzyme
3470.6
ITP
pH 7.5, 25°C, recombinant enzyme, calculated by BRENDA
1370.4
XTP
pH 7.5, 25°C, recombinant enzyme, calculated by BRENDA
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
10.5
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
80
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30 - 90
30°C: about 20% of maximal activity, 90°C: 90% of maximal activity
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
determination of the subcellular localization, overview
-
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
phylogenetic analysis of inosine triphosphate diphosphatase in plants, overview
evolution
the Asian population retains an ITPA variation of about 14% to 19%
evolution
-
the viral inosine triphosphatase (ITPase) belongs to the Ham1 family, CBSV and UCBSV are closely related single-stranded RNA viruses belonging to the Ipomovirus genus. The viral-encoded Ham1 shows sequence motifs typical of ITPase enzymes involved in dephosphorylation of noncanonical nucleotides, atypical nucleotides that arise from oxidative damage or stresses within the purine salvage pathway. It is possible that the viruses acquired the ITPase gene from a host plant by horizontal gene transfer (HGT). HGT between host and virus is predicted to have protective functions through either production of a viral antigen by the host or mimicry of a component of the host immune signalling pathways by the virus
evolution
-
the viral inosine triphosphatase (ITPase) belongis to the Ham1 family. The viral-encoded Ham1 shows sequence motifs typical of ITPase enzymes involved in dephosphorylation of noncanonical nucleotides, atypical nucleotides that arise from oxidative damage or stresses within the purine salvage pathway. It is possible that the viruses acquired the ITPase gene from a host plant by horizontal gene transfer (HGT). HGT between host and virus is predicted to have protective functions through either production of a viral antigen by the host or mimicry of a component of the host immune signalling pathways by the virus
evolution
-
the viral inosine triphosphatase (ITPase) belongis to the Ham1 family, EuRSV belongs to another genus in the Potyviridae family, Potyvirus. The viral-encoded Ham1 shows sequence motifs typical of ITPase enzymes involved in dephosphorylation of noncanonical nucleotides, atypical nucleotides that arise from oxidative damage or stresses within the purine salvage pathway. It is possible that the viruses acquired the ITPase gene from a host plant by horizontal gene transfer (HGT). HGT between host and virus is predicted to have protective functions through either production of a viral antigen by the host or mimicry of a component of the host immune signalling pathways by the virus
malfunction
-
enzyme deficiency results in cell growth suppression and DNA instability. Both growth suppression and accumulation of single-strand breaks in nuclear DNA of enzyme-deficient cells depended on MLH1/PMS2
malfunction
-
enzyme deficiency results in cell growth suppression and DNA instability. Both growth suppression and accumulation of single-strand breaks in nuclear DNA of enzyme-deficient cells depended on MLH1/PMS2
malfunction
ITPA loss-of-function causes inosine di- and triphosphate accumulation in vivo and an elevated inosine and deoxyinosine content in RNA and DNA, respectively, as well as salicylic acid (SA) accumulation, early senescence, and upregulation of transcripts associated with immunity and senescence. Cadmium-induced oxidative stress and biochemical inhibition of the inosine monophosphate dehydrogenase leads to more IDP and ITP in the wild-type, and this effect is enhanced in itpa mutants, suggesting that ITP originates from ATP deamination and IMP phosphorylation. Loss of ITPA leads to an upregulation of transcripts involved in biotic stress
malfunction
the pathological ITPA mutation R178C causes a fatal infantile encephalopathy, termed developmental and epileptic encephalopathy 35 (DEE 35). The enzyme sequence position 178 is essential for ITPA activity and even conservative mutation at this site (R178K) results in significantly reduced enzyme activity. Disruption of the active-site hydrogen bond network is a major cause of diminished ITP hydrolyzing activity for the R178C mutation, which might be useful for therapy of DEE 35
malfunction
ITPA overexpression is implicated in juvenile tuberculosis. ITPase polymorphism (rs1127354) is associated with the hemoglobin level in treated Chinese cohorts suffering hepatitis C, treatment of hepatitic C with interferon alpha and ribavirin can cause haemolytic anaemia. The ITPase P32T mutation is responsible for delaying the conditions responsible for anaemia. ITPase deficiency has a major impact on patients treated with antivirals. Early infantile encephalopathy is caused by a recessive ITPA mutation, R178C, which leads to patients that face seizures, developmental delay, and very serious progressive microcephaly from birth. The heart function is affected resulting in a lower number of RBCs
malfunction
lack of ITPA results in genomic instability and increased levels of inosine in DNA and RNA. The P32T mutation affects roughly 15% of the global population and can modulate treatment outcomes for cancer, lupus, and hepatitis C patients. The R178C mutation is extremely uncommon and has only been reported in a small cohort of early infantile encephalopathy patients suggesting that a functional ITPA protein is essentially required in humans, molecular dynamic simulations, overview
malfunction
polymorphisms of inosine triphosphate diphosphatase (rs1127354 and rs6051702) and interferon lambda 4 (IFLN4) (rs12979860) are indicators of anemia and/or sustained virological response (SVR) in patients with chronic hepatitis C on ribavirin/interferon. The associations of polymorphisms rs1127354 in ITPA, rs6051702 in C20orf194, and rs12979860 in IFNL4 with hemoglobin levels and SVR in patients on ribavirin/interferon treatment are analyzed, development of clinically significant anemia, overviews. Polymorphisms of ITPA and IFNL3 may be associated with the risk of anemia and response to therapy in patients with chronic hepatitis C (CHC)
malfunction
ITPA deficiency sensitizes trypanosomes to inhibition of IMP dehydrogenase (IMPDH). IMPDH catalyzes the NAD+-dependent oxidation of IMP to XMP and is a rate-limiting step in the synthesis of guanine nucleotides. Inactivation of IMPDH has been associated with increased accumulation of inosine in RNA and DNA in bacteria. Knockdown of ITPA by RNAi does not cause significant loss of fitness in BSF or PCF (procyclic forms) parasites. Parasites lacking TbITPA exhibit a similar proliferation rate than parental BSF cells or KO cells expressing myc TbITPA. Knockout cells deficient in ITPase activity are significantly less sensitive to RBV than parental or knockout cells expressing TbITPA from a different locus. Intracellular RTP levels do not seem to correlate with defective proliferation
malfunction
mutations in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Molecular basis for ITPA-associated pathogenesis, evidence for RNA dysfunction, clinically relevant ITPA variants, phenotypes, overview
malfunction
-
ITPA deficiency sensitizes trypanosomes to inhibition of IMP dehydrogenase (IMPDH). IMPDH catalyzes the NAD+-dependent oxidation of IMP to XMP and is a rate-limiting step in the synthesis of guanine nucleotides. Inactivation of IMPDH has been associated with increased accumulation of inosine in RNA and DNA in bacteria. Knockdown of ITPA by RNAi does not cause significant loss of fitness in BSF or PCF (procyclic forms) parasites. Parasites lacking TbITPA exhibit a similar proliferation rate than parental BSF cells or KO cells expressing myc TbITPA. Knockout cells deficient in ITPase activity are significantly less sensitive to RBV than parental or knockout cells expressing TbITPA from a different locus. Intracellular RTP levels do not seem to correlate with defective proliferation
-
malfunction
Trypanosoma brucei brucei 4GUTat10.1
-
ITPA deficiency sensitizes trypanosomes to inhibition of IMP dehydrogenase (IMPDH). IMPDH catalyzes the NAD+-dependent oxidation of IMP to XMP and is a rate-limiting step in the synthesis of guanine nucleotides. Inactivation of IMPDH has been associated with increased accumulation of inosine in RNA and DNA in bacteria. Knockdown of ITPA by RNAi does not cause significant loss of fitness in BSF or PCF (procyclic forms) parasites. Parasites lacking TbITPA exhibit a similar proliferation rate than parental BSF cells or KO cells expressing myc TbITPA. Knockout cells deficient in ITPase activity are significantly less sensitive to RBV than parental or knockout cells expressing TbITPA from a different locus. Intracellular RTP levels do not seem to correlate with defective proliferation
-
metabolism
-
inosine triphosphatases (ITPases) are highly conserved enzymes that occur in all kingdoms of life and perform a house-cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate
metabolism
-
inosine triphosphatases (ITPases) are highly conserved enzymes that occur in all kingdoms of life and perform a house-cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate
metabolism
-
inosine triphosphatases (ITPases) are highly conserved enzymes that occur in all kingdoms of life and perform a house-cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate
metabolism
ITPase levels modulate ribavirin metabolism and toxicity in trypanosomes. Ribavirin (RBV) is an antiviral purine nucleoside analogue with in vitro activity against a broad spectrum of RNA and DNA viruses. The bioactivated form of RBV, ribavirin triphosphate, is hydrolyzed by Trypanosoma brucei ITPA with similar efficiency as its natural substrate ITP. Ribavirin 5'-monophosphate (RMP) is a potent TbIMPDH inhibitor
metabolism
the enzyme is involved in de novo purine nucleotide biosynthesis, overview
metabolism
-
ITPase levels modulate ribavirin metabolism and toxicity in trypanosomes. Ribavirin (RBV) is an antiviral purine nucleoside analogue with in vitro activity against a broad spectrum of RNA and DNA viruses. The bioactivated form of RBV, ribavirin triphosphate, is hydrolyzed by Trypanosoma brucei ITPA with similar efficiency as its natural substrate ITP. Ribavirin 5'-monophosphate (RMP) is a potent TbIMPDH inhibitor
-
metabolism
Trypanosoma brucei brucei 4GUTat10.1
-
ITPase levels modulate ribavirin metabolism and toxicity in trypanosomes. Ribavirin (RBV) is an antiviral purine nucleoside analogue with in vitro activity against a broad spectrum of RNA and DNA viruses. The bioactivated form of RBV, ribavirin triphosphate, is hydrolyzed by Trypanosoma brucei ITPA with similar efficiency as its natural substrate ITP. Ribavirin 5'-monophosphate (RMP) is a potent TbIMPDH inhibitor
-
physiological function
the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
physiological function
RNA and DNA from Arabidopsis thaliana contain (deoxy)inosine, probably derived from non-enzymatic adenosine deamination in nucleic acids and usage of (deoxy)inosine triphosphate (dITP and ITP) during nucleic acid synthesis. Inosine triphosphate diphosphatase dephosphorylates deaminated nucleoside di- and triphosphates to the respective monophosphates. Inosine triphosphate diphosphatase is part of a molecular protection system in plants, preventing the accumulation of (d)ITP and its usage for nucleic acid synthesis. ITPA prevents (d)ITP incorporation into DNA and RNA. ITPA is essential for the catabolism of ITP and IDP in vivo
physiological function
a study of ITPA expression in the thymus gland shows that it may have a very strong role in the development and outbreak of tuberculosis. Role of ITPase in genomic stability and cancer, overview
physiological function
the inosine triphosphate diphosphatase (ITPA) is responsible for removing noncanonical purine nucleoside triphosphates from intracellular nucleotide pools thereby playing a protective role in the cell
physiological function
-
ITPase Ham1 in (U)CBSV and EuRSV perform a house-cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate. The enzyme is implicated to play an important role in the pathogenesis of these viruses because not only is it unusual for plant viruses to acquire additional genes, but in this case the same type of gene has appeared in different genera. The enzyme is implicated to play an important role in the pathogenesis of the virus. Viral ITPase is an ITPase, but possibly not a suppressor of mutation. No significant difference in mutation rates between wild-type and Ham1-expressing Nicotiana benthamiana plants. Importance of the enzyme in depletion of mutagenic pools of noncanonical nucleotide triphosphates (NTPs). Possible roles for viral HAM1, three possibilities are discussed: 1. reduction of mutation load, 2. disruption of plant signalling pathways, and 3. reduction of ITP antagonistic/agonistic interactions with nucleotide-binding proteins, overview
physiological function
-
ITPase Ham1 in (U)CBSV and EuRSV perform a house-cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate. The enzyme is implicated to play an important role in the pathogenesis of these viruses because not only is it unusual for plant viruses to acquire additional genes, but in this case the same type of gene has appeared in different genera. The enzyme is implicated to play an important role in the pathogenesis of the virus. Viral ITPase is an ITPase, but possibly not a suppressor of mutation. No significant difference in mutation rates between wild-type and Ham1-expressing Nicotiana benthamiana plants. Importance of the enzyme in depletion of utageneic pools of noncanonical nucleotide triphosphates (NTPs). Possible roles for viral HAM1, three possibilities are discussed: 1. reduction of mutation load, 2. disruption of plant signalling pathways, and 3. reduction of ITP antagonistic/agonistic interactions with nucleotide-binding proteins, overview
physiological function
-
ITPase Ham1 in (U)CBSV and EuRSV perform a house-cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate. The enzyme is implicated to play an important role in the pathogenesis of these viruses because not only is it unusual for plant viruses to acquire additional genes, but in this case the same type of gene has appeared in different genera. The enzyme is implicated to play an important role in the pathogenesis of the virus. Viral ITPase is an ITPase, but possibly not a suppressor of mutation. No significant difference in mutation rates between wild-type and Ham1-expressing Nicotiana benthamiana plants. Importance of the enzyme in depletion of utageneic pools of noncanonical nucleotide triphosphates (NTPs). Possible roles for viral HAM1, three possibilities are discussed: 1. reduction of mutation load, 2. disruption of plant signalling pathways, and 3. reduction of ITP antagonistic/agonistic interactions with nucleotide-binding proteins, overview
physiological function
inosine triphosphate diphosphatases (ITPases) are ubiquitous house-cleaning enzymes that specifically recognize deaminated purine nucleotides and catalyze their hydrolytic cleavage. The primary role of TbITPA is the exclusion of deaminated purines from the cytosolic nucleoside triphosphate pools. The enzyme is responsible for the conversion of noncanonical (d)ITP and XTP nucleotides into their respective monophosphate forms and diphosphate. TbITPA is not essential in Trypanosoma brucei bloodstream forms (BSF)
physiological function
incorporation of noncanonical nucleotide triphosphates into nucleic acids during their synthesis is generally avoided because of its potential to impair the faithful reproduction of genetic information. Because these nucleotides may be generated as consequence of normal metabolism, and may act as substrates for polymerase enzymes, they are actively excluded from cellular nucleotide pools. ITPase catalyzes hydrolysis of several such noncanonical purine (d)NTPs, including ITP, dITP, XTP, and dXTP. Unlike the hydrolysis of the canonical nucleotides like ATP and GTP by ATPases and GTPases, which is widely integrated into cellular function in coupled reactions, that of (d)ITP and (d)XTP is not underlining their position as contaminants
physiological function
-
the enzyme hydrolyzes the non-canonical nucleotides, dITP and XTP and may have a major role in preventing mutations caused by incorporation of dITP and XTP formed spontaneously in the nucleotide pool into DNA
-
physiological function
-
inosine triphosphate diphosphatases (ITPases) are ubiquitous house-cleaning enzymes that specifically recognize deaminated purine nucleotides and catalyze their hydrolytic cleavage. The primary role of TbITPA is the exclusion of deaminated purines from the cytosolic nucleoside triphosphate pools. The enzyme is responsible for the conversion of noncanonical (d)ITP and XTP nucleotides into their respective monophosphate forms and diphosphate. TbITPA is not essential in Trypanosoma brucei bloodstream forms (BSF)
-
physiological function
Trypanosoma brucei brucei 4GUTat10.1
-
inosine triphosphate diphosphatases (ITPases) are ubiquitous house-cleaning enzymes that specifically recognize deaminated purine nucleotides and catalyze their hydrolytic cleavage. The primary role of TbITPA is the exclusion of deaminated purines from the cytosolic nucleoside triphosphate pools. The enzyme is responsible for the conversion of noncanonical (d)ITP and XTP nucleotides into their respective monophosphate forms and diphosphate. TbITPA is not essential in Trypanosoma brucei bloodstream forms (BSF)
-
additional information
position 178 of the enzyme sequence is essential for ITPA activity. Arg178 is located in the substrate specificity pocket of ITPA and its terminal guanidino group makes critical noncovalent interactions with the incoming ITP substrate, which is thought to contribute to substrate specificity
additional information
wild-type enzyme structure and dynamics, and function, molecular dynamic simulations, key hydrogen bond interactions and residues in the active site for enzyme activity, detailed overview
Show AA Sequence and Transmembrane Helices (23306 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
tetramer
homodimer
-
ITPases belonging to the Maf/Ham1 superfamily exist as homodimers and possess a beta-sheet backbone from which two alpha-helix lobes extend, forming a substrate-binding cleft
homodimer
-
ITPases belonging to the Maf/Ham1 superfamily exist as homodimers and possess a beta-sheet backbone from which two alpha-helix lobes extend, forming a substrate-binding cleft
homodimer
-
ITPases belonging to the Maf/Ham1 superfamily exist as homodimers and possess a beta-sheet backbone from which two alpha-helix lobes extend, forming a substrate-binding cleft
tetramer
crystal structure shows a tetramer with two possible dimer interfaces
tetramer
-
crystal structure shows a tetramer with two possible dimer interfaces
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure analysis of ITP in complex with human inosine triphosphatase, overview
crystals are grown by hanging-drop vapor diffusion method, the crystal structure of the protein is determined at 2.2 A resolution
oil microbatch method. High resolution crystal structures of the enzyme in two unliganded forms and in three liganded forms with the substrate ITP, the product IMP and the divalent cation Mn2+ are determined. Based on these structures, a mechanism of the divalent cation-dependent ITP hydrolysis is proposed
protein X-ray structure of the enzyme with bound IMP is obtained at 2.15 A resolution and compare it with structures of unliganded TM0159 and other noncanonical NTPases
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
P32T
R178C
R178K
site-directed mutagenesis, the mutant shows highly reduced activity with ITP compared to wild-type
R178S
site-directed mutagenesis, the mutant shows highly reduced activity with ITP compared to wild-type
additional information
P32T
naturally occurring mutation, the mutant shows highly reduced enzyme activity, phenotype
R178C
naturally occurring mutation, the mutant shows highly reduced ITP hydrolyzing activity. The accumulation of noncanonical nucleotides such as inosine triphosphate (ITP), is suspected to affect RNA and/or interfere with normal nucleotide function, leading to development of DEE 35. The very rare R178C mutation does not significantly perturb the overall structure of the protein, but results in a high level of structural flexibility and disrupts active-site hydrogen bond networks, while preliminary biochemical data indicate that ITP hydrolyzing activity is significantly reduced for the R178C mutant, molecular dynamics simulations, overview
R178C
naturally occurring mutation, the mutant shows highly reduced enzyme activity, phenotype. The mutant shows structural difference to the wild-type enzyme
additional information
two T-DNA insertion ITPA mutants (itpa-1 and itpa-2) show an early onset senescence phenotype. Loss-of-function of itpa causes an accumulation of inosine diphosphate (IDP) and inosine triphosphate (ITP), while adenylate concentrations remain unchanged. Overexpression of ITPA (itpa-2::C) leads to a concentration of deoxyinosine comparable to what is measured in wild-type plants. Loss of ITPA leads to an upregulation of transcripts involved in biotic stress
additional information
molecular dynamic simulations that describe the structure and dynamics of the wild-type ITPA homodimer and two of its clinically relevant mutants, P32T and R178C. The simulation results indicate that both the P32T and R178C mutations alter the structure and dynamic properties of the protein and provide a possible explanation of the experimentally observed effect of the mutations on ITPA activity. Specifically, the mutations increase the overall flexibility of the protein and change the dominant collective motions of the top lobe as well as the helix 2 of the lower lobe
additional information
biallelic loss-of-function ITPA variants show severe or complete loss of ITPase activity causing fatal infantile neurodevelopmental disorder
additional information
knockdown of ITPA by RNAi does not cause significant loss of fitness in BSF or PCF (procyclic forms) parasites. Parasites lacking TbITPA exhibit a similar proliferation rate than parental BSF cells or KO cells expressing myc-TbITPA. Knockout cells deficient in ITPase activity are significantly less sensitive to RBV than parental or knockout cells expressing TbITPA from a different locus. Intracellular RTP levels do not seem to correlate with defective proliferation
additional information
Trypanosoma brucei brucei 4GUTat10.1
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knockdown of ITPA by RNAi does not cause significant loss of fitness in BSF or PCF (procyclic forms) parasites. Parasites lacking TbITPA exhibit a similar proliferation rate than parental BSF cells or KO cells expressing myc-TbITPA. Knockout cells deficient in ITPase activity are significantly less sensitive to RBV than parental or knockout cells expressing TbITPA from a different locus. Intracellular RTP levels do not seem to correlate with defective proliferation
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additional information
-
knockdown of ITPA by RNAi does not cause significant loss of fitness in BSF or PCF (procyclic forms) parasites. Parasites lacking TbITPA exhibit a similar proliferation rate than parental BSF cells or KO cells expressing myc-TbITPA. Knockout cells deficient in ITPase activity are significantly less sensitive to RBV than parental or knockout cells expressing TbITPA from a different locus. Intracellular RTP levels do not seem to correlate with defective proliferation
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
thermostability is highest near 300 mM NaCl
additional information
-
thermostability is highest near 300 mM NaCl
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant C-terminally strep-tagged enzyme ITPA from Nicotiana benthamiana leaves by affinity chromatography
recombinant His6-tagged wild-type ITPA and mutant R178C enzymes by nickel affinity chromatography and dialysis
recombinant N-terminally His6-tagged enzyme from Escherichia coli by nickel affinity chromatography and anion exchange chromatography to near homogeneity
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene ITPA, genetic structure, overview
gene ITPA, phylogenetic analysis, recombinant overexpression of C-terminally strep-tagged enzyme ITPA in Nicotiana benthamiana leaves, C-terminally YFP-tagged enzyme is transiently coexpressed with a construct encoding cytosolic bureidopropionase C-terminally fused to CFP
gene ITPA, recombinant expression of His6-tagged wild-type ITPA and mutant R178C enzymes
TbITPA, recombinant expression of N-terminally His6-tagged enzyme in Escherichia coli, recombinant expression of N-terminally myc-tagged enzyme
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
expression of ITPA itself is not influenced by a treatment with salicylic acid
treating wild-type plants with cadmium sulfate results in a minor, but significant, decrease in ITPA transcript abundance
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Chung, J.H.; Back, J.H.; Park, Y.I.; Han, Y.S.
Biochemical characterization of a novel hypoxanthine/xanthine dNTP pyrophosphatase from Methanococcus jannaschii
Nucleic Acids Res.
29
3099-3107
2001
Archaeoglobus fulgidus (O28046), Archaeoglobus fulgidus, Escherichia coli, Methanocaldococcus jannaschii (Q57679), Methanocaldococcus jannaschii, Methanocaldococcus jannaschii DSM 2661 (Q57679)
brenda
Hwang, K.Y. Chung, J.H.; Kim, S.H.; Han, Y.S.; Cho, Y.
Structure-based identification of a novel NTPase from Methanococcus jannaschii
Nat. Struct. Biol.
6
691-696
1999
Methanocaldococcus jannaschii (Q57679), Methanocaldococcus jannaschii, Methanocaldococcus jannaschii DSM 2661 (Q57679)
brenda
Lokanath, N.; Pampa, K.; Takio, K.; Kunishima, N.
Structures of dimeric nonstandard nucleotide triphosphate pyrophosphatase from Pyrococcus horikoshii OT3 functional significance of interprotomer conformational changes
J. Mol. Biol.
375
1013-1025
2008
Pyrococcus horikoshii (O59580), Pyrococcus horikoshii OT-3 (O59580)
brenda
Awwad, K.; Desai, A.; Smith, C.; Sommerhalter, M.
Structural and functional characterization of a noncanonical nucleoside triphosphate pyrophosphatase from Thermotoga maritima
Acta Crystallogr. Sect. D
69
184-193
2013
Thermotoga maritima (Q9WY06), Thermotoga maritima DSM 3109 (Q9WY06)
brenda
Dushanov, E.; Koltovaya, N.
Effect of substitution pro32Thr on the interaction between dimer subunits of human phosphatase ITPA
Curr. Enzyme Inhib.
15
46-54
2019
Homo sapiens (Q9BY32)
-
brenda
Yoneshima, Y.; Abolhassani, N.; Iyama, T.; Sakumi, K.; Shiomi, N.; Mori, M.; Shiomi, T.; Noda, T.; Tsuchimoto, D.; Nakabeppu, Y.
Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells
Sci. Rep.
6
32849
2016
Homo sapiens, Mus musculus
brenda
Burgis, N.E.; April, C.; VanWormer, K.
Arginine-178 is an essential residue for ITPA function
Arch. Biochem. Biophys.
744
109700
2023
Homo sapiens (Q9BY32)
brenda
Zamzami, M.A.
Inosine triphosphate pyrophosphatase (ITPase) functions, mutations, polymorphisms and its impact on cancertherapies
Cells
11
384
2022
Homo sapiens (Q9BY32)
brenda
Houndonougbo, Y.; Pugh, B.; VanWormer, K.; April, C.; Burgis, N.
Structural dynamics of inosine triphosphate pyrophosphatase (ITPA) protein and two clinically relevant mutants molecular dynamics simulations
J. Biomol. Struct. Dyn.
39
1236-1247
2021
Homo sapiens (Q9BY32)
brenda
Chi, X.; Wang, M.; Pan, Y.; Jiang, J.; Jiang, T.; Yan, H.; Wu, R.; Wang, X.; Gao, X.; Niu, J.
Inosine triphosphate pyrophosphatase polymorphisms are predictors of anemia in Chinese patients with chronic hepatitis C during therapy with ribavirin and interferon
J. Gastroenterol. Hepatol.
35
97-103
2020
Homo sapiens (Q9BY32)
brenda
James, A.M.; Seal, S.E.; Bailey, A.M.; Foster, G.D.
Viral inosine triphosphatase a mysterious enzyme with typical activity, but an atypical function
Mol. Plant Pathol.
22
382-389
2021
Cassava brown streak virus, Euphorbia ringspot virus, Ugandan cassava brown streak virus
brenda
Straube, H.; Straube, J.; Rinne, J.; Fischer, L.; Niehaus, M.; Witte, C.P.; Herde, M.
An inosine triphosphate pyrophosphatase safeguards plant nucleic acids from aberrant purine nucleotides
New Phytol.
237
1759-1775
2023
Arabidopsis thaliana (Q8L968)
brenda
Vidal, A.E.; Yaguee-Capilla, M.; Martinez-Arribas, B.; Garcia-Caballero, D.; Ruiz-Perez, L.M.; Gonzalez-Pacanowska, D.
Inosine triphosphate pyrophosphatase from Trypanosoma brucei cleanses cytosolic pools from deaminated nucleotides
Sci. Rep.
12
6408
2022
Trypanosoma brucei brucei (Q389X7), Trypanosoma brucei brucei 4GUTat10.1 (Q389X7), Trypanosoma brucei brucei TREU927 (Q389X7)
brenda
Schroader, J.H.; Handley, M.T.; Reddy, K.
Inosine triphosphate pyrophosphatase a guardian of the cellular nucleotide pool and potential mediator of RNA function
Wiley Interdiscip. Rev. RNA
14
e1790
2023
Homo sapiens (Q9BY32)
brenda
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