The purine bases guanine and hypoxanthine (derived from adenine by events in the purine salvage pathways) are converted to xanthine and then to uric acid, which is excreted from the body (Watts 1974). The end-point of this pathway in humans and hominoid primates is unusual. Most other mammals metabolize uric acid further to yield more soluble end products, and much speculation has centered on possible roles for high uric acid levels in normal human physiology.
In parallel sequences of three reactions each, the pyrimidines thymine and uracil are converted to beta-aminoisobutyrate and beta-alanine respectively. Both of these molecules are excreted in human urine and appear to be normal end products of pyrimidine catabolism (Griffith 1986). Mitochondrial AGXT2, however, can also catalyze the transamination of both molecules with pyruvate, yielding 2-oxoacids that can be metabolized further by reactions of branched-chain amino acid and short-chain fatty acid catabolism (Tamaki et al. 2000).<p>Hydrolysis of phosphate bonds in nucleotides catalyzed by members of the NUDT and NTPD families of enzymes have been grouped here as well, although the physiological roles of these groups of catabolic reactions are diverse.
View original pathway at:Reactome.</div>
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Yokota H, Fernandez-Salguero P, Furuya H, Lin K, McBride OW, Podschun B, Schnackerz KD, Gonzalez FJ.; ''cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria.''; PubMedEurope PMCScholia
Fujikawa K, Kamiya H, Yakushiji H, Fujii Y, Nakabeppu Y, Kasai H.; ''The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein.''; PubMedEurope PMCScholia
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Takagi Y, Setoyama D, Ito R, Kamiya H, Yamagata Y, Sekiguchi M.; ''Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2.''; PubMedEurope PMCScholia
Four NUDT1 ("MTH1") proteins have been identified, generated from a single gene by use of alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been biochemically characterized and shown to catalyze hydrolysis of 8-oxo-dGTP (Sakumi et al. 1993). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well though they have not been experimentally characterized.
5'-nucleotidase (NT5E) associated with the plasma membrane catalyzes the reactions of extracellular AMP, dAMP, GMP, or IMP with H2O to yield the corresponding nucleoside and orthophosphate. The active enzyme is a glycolipid-anchored dimer (Misumi et al. 1990; Thompson et al. 1987; Zimmerman 1992)
5'-nucleotidase (NT5E) associated with the plasma membrane catalyzes the reactions of extracellular CMP, TMP, or UMP with H2O to yield the corresponding nucleoside and orthophosphate. The active enzyme is a glycolipid-anchored dimer (Misumi et al. 1990; Thompson et al. 1987; Zimmerman 1992)
Cytosolic 5'-nucleotidase IA (NT5C1A) catalyzes the hydrolysis of (deoxy)cytidine monophosphate, thymidine monophosphate and (deoxy)uridine monophosphate to the corresponding nucleosides plus orthophosphate. The enzyme is allosterically activated by ADP (Hunsucker et al. 2001). The human enzyme is inferred to be a homotetramer with one Mg++ ion bound per subunit based on its similarity to the pigeon heart enzyme (Bianchi and Spychala 2003; Sala-Newby et al. 1999; Skladanowski and Newby 1990).
Cytosolic 5'-nucleotidase IA catalyzes the hydrolysis of purine ribo- and deoxyribonucleoside monophosphates to nucleosides plus orthophosphate. The enzyme is allosterically activated by ADP (Hunsucker et al. 2001). The human enzyme is inferred to be a homotetramer with one Mg++ ion bound per subunit, based on its similarity to the pigeon heart enzyme (Bianchi and Spychala 2003; Sala-Newby et al. 1999; Skladanowski and Newby 1990).
5'-nucleotidase cytosolic IB catalyzes the hydrolysis of AMP to yield adenosine and orthophosphate. The human enzyme has been identified as the product of a recombinant DNA clone, but its biochemical properties are largely inferred from those of the better studied mouse and rat enzymes (Sala-Newby and Newby 2001; Sala-Newby et al. 2003).
Cytosolic 5'-nucleotidase 3 (NT5C3) catalyzes the hydrolysis of pyrimidine nucleoside monophosphates (d)CMP, TMP, and (d)UMP to nucleosides plus orthophosphate. While the enzyme appears to be present in many tissues, it is especially abundant in erythrocytes, where it may function to remove excess pyrimidine nucleotides generated by nucleic acid breakdown, while sparing purine nucleotides needed for red cell energy metabolism. Deficiencies in the enzyme are associated with a form of hemolytic anemia and its inactivation by heavy metals may be responsible for some hematological abnormalities associated with lead poisoning (Marinaki et al. 2001; Rees et al. 2003). The active form of the enzyme is a monomer. It has an absolute requirement for Mg++, and is inactive against purine nucleotides (Amici et al. 1997; Amici and Magni 2002).
Cytosolic 5'3'-nucleotidase (NT5C) catalyzes the hydrolysis of deoxy- and ribo- guanosine and inosine nucleoside monophosphates to yield the corresponding nucleosides and orthophosphate. The active form of the enzyme is a homodimer, with an absolute requirement for Mg++ (Hoglund and Reichard 1990; Rampazzo et al. 2000). This enzyme appears to play a central role in the "substrate cycles" that regulate cytosolic deoxynucleotide levels (Gazziola et al. 2001).
Cytosolic 5'3'-nucleotidase (NT5C) catalyzes the hydrolysis of uridine 2', 3', and 5' monophosphates, dexoyuridine 3' and 5' monophosphates, and thymidine monophosphate to yield the corresponding (deoxy)nucleosides and orthophosphate. The active form of the enzyme is a homodimer, with an absolute requirement for Mg++ (Hoglund and Reichard 1990; Rampazzo et al. 2000). This enzyme appears to play a central role in the "substrate cycles" that regulate cytosolic deoxynucleotide levels (Gazziola et al. 2001).
5'3'-Nucleotidase, mitochondrial (NT5M) is the major nucleotidase of human mitochondria, catalyzing the hydrolysis of TMP, uridine 2'-, 3'-, and 5'-monophosphates, and dUMP to yield the corresponding (deoxy)nucleosides and orthophosphate. It may play a central role in "substrate cycles" to regulate mitochondrial deoxynucleotide levels, especially in non-dividing cells (Rampazzo et al. 2000; Gallinaro et al. 2002). The active form of the enzyme is a homodimer, with an absolute requirement for Mg++ (Rampazzo et al. 2000; Rinaldo-Matthis et al. 2002).
Cytosolic thymidine phosphorylase (TYMP) catalyzes the reversible reactions of thymidine or deoxyuridine with orthophosphate to form thymine or uracil and 2-deoxy-D-ribose 1-phosphate. The active form of the enzyme is a homodimer (Desgranges et al. 1981; Norman et al. 2004; Usuki et al. 1992).
Cytosolic NUDT5 dimer (ADP-ribose pyrophosphatase) catalyzes the hydrolysis of ADP-ribose to form AMP and D-ribose 5-phosphate. Each NUDT5 subunit is associated with three magnesium ions (Zha et al. 2006, 2008). NUDT5 also catalyzes the hydrolysis of 8-oxo-dGTP but with a strongly alkaline pH optimum (Ito et al. 2011) so the physiological relevance of this reaction is unclear and it is not annotated here.
Mitochondrial NUDT9 (ADP-ribose pyrophosphatase) catalyzes the hydrolysis of ADP-ribose to form AMP and D-ribose 5-phosphate. The active enzyme is the longer of two isoforms generated by alternative splicing and is a monomer complexed with two magnesium ions (Perraud et al. 2003; Shen et al. 2003).
NUDT1 (MTH1) catalyzes the reaction of 2-hydroxy-dATP and water to form 2-hydroxy-dAMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been shown to catalyze hydrolysis of 2-hydroxy-dATP (Fujikawa et al. 1993; Sakai et al. 2002). The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995). Its expression prevents the accumulation of modified adenosine bases in DNA in mutant mouse cells lacking endogenous NUDT1 activity (Yoshimura et al. 2003).
Together, these data support the hypothesis that by cleaving 2-hydroxy-dATP and thus preventing its incorporation into DNA, NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress. This hypothesis is further supported by the demonstration that mice lacking NUDT1 show an increased lifetime incidence of liver and other tumors compared to normal controls, and that rapidly metabolizing tumor cells in culture are killed under conditions where synthesis of NUDT1 protein is suppressed or its catalytic activity is inhibited (Gad et al. 2014; Huber et al. 2014).
NUDT1 (MTH1) catalyzes the reaction of 8-oxo-dGTP and water to form 8-oxo-dGMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been biochemically (Sakumi et al. 1993; Takagi et al. 2012) and structurally (Mishima et al. 2004) characterized and shown to catalyze hydrolysis of 8-oxo-dGTP. The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995). Its expression prevents the accumulation of oxo-guanine bases in DNA in mutant mouse cells lacking endogenous NUDT1 activity (Yoshimura et al. 2003).
Together, these data support the hypothesis that by cleaving 8-oxo-dGTP and thus preventing its incorporation into DNA NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress. This hypothesis is further supported by the demonstration that mice lacking NUDT1 show an increased lifetime incidence of liver and other tumors compared to normal controls, and that rapidly metabolizing tumor cells in culture are killed under conditions where synthesis of NUDT1 protein is suppressed or its catalytic activity is inhibited (Gad et al. 2014; Huber et al. 2014).
NUDT15 (MTH2) catalyzes the reaction of 8-oxo-dGTP and water to form 8-oxo-dGMP and PPi (pyrophosphate). Cai et al. (2003) first identified this activity in studies of the homologous mouse protein; the activity of the human NUDT15 protein has since been confirmed experimentally (Takagi et al. 2012).
NUDT1 (MTH1) catalyzes the reaction of 2-hydroxy-ATP and water to form 2-hydroxy-AMP and PPi (pyrophosphate). Four NUDT1 proteins have been identified, encoded by a single gene with alternative start codons (Oda et al. 1999). The shortest of these, NUDT1 p18, has been shown to catalyze hydrolysis of 2-hydroxy-dATP (Fujikawa et al. 2001). The active enzyme is a monomer associated with a magnesium ion (Mishima et al. 2004). The longer isoforms all consist of the p18 polypeptide with aminoterminal extensions and are presumed to be active as well, but have not been experimentally characterized. The p18 isoform is predominantly cytosolic (Kang et al. 1995).
NUDT18 (MTH3) catalyzes the reaction of 8-oxo-GDP and water to form 8-oxo-GMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT18 has not been established but is assumed to be cytosolic like NUDT1.
NUDT15 (MTH2) catalyzes the reaction of 8-oxo-dGDP and water to form 8-oxo-dGMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT15 has not been established but is assumed to be cytosolic like NUDT1.
NUDT18 (MTH3) catalyzes the reaction of 8-oxo-dGDP and water to form 8-oxo-dGMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT18 has not been established but is assumed to be cytosolic like NUDT1.
NUDT18 (MTH3) catalyzes the reaction of 8-hydroxy-dADP and water to form 8-hydroxy-dAMP and Pi (orthophosphate) (Takagi et al. 2012). The subcellular location of NUDT18 has not been established but is assumed to be cytosolic like NUDT1.
NUDT16 dimer catalyzes the reaction of dIDP and water to form dIMP and Pi (orthophosphate). Mg++ is required for enzymatic activity. The protein is mostly located in the nucleus and concentrated in the nucleolus, where it can also mediate the decapping of U8 small nucleolar RNA (Iyama et al. 2010; Peculis et al. 2007).
NUDT16 dimer catalyzes the reaction of IDP and water to form IMP and Pi (orthophosphate). Mg++ is required for enzymatic activity. The protein is mostly located in the nucleus and concentrated in the nucleolus, where it can also mediate the decapping of U8 small nucleolar RNA (Iyama et al. 2010; Peculis et al. 2007).
Cytosolic ITPA dimer catalyzes the reaction of ITP and water to form IMP and PPi (pyrophosphate). Mg++ is required for enzymatic activity. The hydrolysis of ITP is thought to prevent its incorporation into mRNA, which would lead to aberrant protein synthesis (Lin et al. 2001; Abolhassani et al. 2010).
Cytosolic ITPA dimer catalyzes the reaction of XTP and water to form XMP and PPi (pyrophosphate). Mg++ is required for enzymatic activity. The hydrolysis of XTP is thought to prevent its incorporation into mRNA, which would lead to aberrant protein synthesis (Lin et al. 2001; Abolhassani et al. 2010).
Cytosolic ITPA dimer catalyzes the reaction of dITP and water to form dIMP and PPi (pyrophosphate). Mg++ is required for enzymatic activity. The hydrolysis of dITP is thought to prevent its incorporation into DNA, which would be mutagenic (Lin et al. 2001; Abolhassani et al. 2010).
Manganese-dependent ADP-ribose/CDP-alcohol diphosphatase (ADPRM:Mn2+) can mediate the hydrolysis of ADP-ribose and less efficiently, CDP-alcohols and 2',3'-cAMP (Cabezas et al. 2015).
Cytosolic glutathione peroxidase (GPX1) tetramer catalyzes the reaction of reduced glutathione and hydrogen peroxide to form reduced glutathione and water (Chu et al. 1993).
Cytosolic dihydropyrimidine dehydrogenase catalyzes the reaction of uracil and NADPH + H+ to form 5,6-dihydrouracil and NADP+. The mechanism of the human reaction is inferred from that of the well-characterized pig enzyme (Yokota et al. 1994).
Cytosolic dihydropyrimidine dehydrogenase catalyzes the reaction of thymine and NADPH + H+ to form 5,6-dihydrothymine and NADP+. The mechanism of the human reaction is inferred from that of the well-characterized pig enzyme (Yokota et al. 1994).
Cytosolic UPB1 (beta-ureidopropionase) catalyzes the reaction of 3-ureidoisobutyrate and H2O to form (R)-3-aminoisobutyrate, CO2, and NH3 (Tamaki et al. 2000; van Kuilenburg et al. 2004).
Cytosolic nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of inosine or deoxyinosine with orthophosphate to form hypoxanthine and ribose 1-phosphate or deoxyribose 1-phosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either nuckeotide in vitro, levels of deoxyinosine are normally low in vivo, limiting the extent of this reaction. NP deficiency in vivo is associated with defects in purine nucleotide salvage and leads to immunodeficiency (Williams et al. 1987).
Cytosolic xanthine dehydrogenase (XDH) catalyzes the reaction of hypoxanthine with H2O and oxygen to form xanthine and H2O2. The active form of the enzyme is a dimer (Saksela and Raivio 1996; Yamaguchi et al. 2007).
Cytosolic purine 5'-nucleotidase (NT5C2) catalyzes the hydrolysis of GMP, dGMP, IMP, and dIMP to yield the corresponding nucleosides and orthophosphate (Bianchi and Spychala 2003; Spychala et al. 1988). The active form of the enzyme is a tetramer and has an absolute requirement for magnesium ions (Spychala et al. 1988; Wallden et al. 2007). Consistent with the biochemical properties of purified enzyme, cultured cells overexpressing the enzyme from a recombinant DNA clone showed enhanced activity against inosine and guanosine monophosphates, but not adenosine monophosphate (Gazziola et al. 2001; Sala-Newby et al. 2000).
Cytosolic nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of guanosine or deoxyguanosine with orthophosphate to form guanine and ribose 1-phosphate or deoxyribose 1-phosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either nuckeotide in vitro, levels of deoxyguanosine are normally low in vivo, limiting the extent of this reaction. NP deficiency in vivo is associated with defects in purine nucleotide salvage and leads to immunodeficiency (Williams et al. 1987).
Cytosolic guanine deaminase (GDA) catalyzes the reaction of guanine and water to form xanthine and ammonia (Yuan et al. 1999). The active enzyme is a homodimer (Murphy et al. 2009).
Cytosolic xanthine dehydrogenase (XDH) catalyzes the reaction of xanthine with H2O to form urate and H2O2. The active form of the enzyme is a dimer (Saksela and Raivio 1996; Yamaguchi et al. 2007).
Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) catalyzes the reversible reactions of uridine or deoxyuridine with orthophosphate to yield uracil and ribose 1-phosphate or deoxyribose 1-phosphate (Watanabe and Uchida 1995; Johansson, 2003). The active form of UPP1 is a dimer (Rooslid et al. 2009).
NTPDase1 (CD39) is a plasma membrane-bound ectonucleotidase encoded by the ENTPD1 gene that hydrolyzes extracellular NTPs to NMPs, via corresponding NDP intermediates (Lemmens et al. 2000, Kukulski et al. 2005). NTPDase1 is expressed on endothelial cells, smooth muscle cells and most leukocytes. The vascular endothelial NTPDase1 regulates platelet aggregation and thrombosis (Kaczmarek et al. 1996, Enjoyji et al. 1999). In mice, NTPDase1 is expressed at the surface of epidermal dendritic cells (Langerhans cells) and is involved in regulation of immune response to skin irritants (Mizumoto et al. 2002). NTPDase1 expressed in vascular smooth muscle cells regulates vasomotion (Kauffenstein et al. 2010, reviewed by Kukulski et al. 2011). In regulatory T lymphocytes (Tregs) and other leukocytes NTPDase1 regulates inflammatory processes (Deaglio et al. 2007).
NTPDase1 (CD39), a plasma membrane-bound nucleotide phosphatase encoded by the ENTPD1 gene, hydrolyzes extracellular NDPs to corresponding NMPs (Lemmens et al. 2000, Kukulski et al. 2005) which contributes to inhibition of platelet aggregation and thrombosis (Kaczmarek et al. 1996, Enjyoji et al. 1999, Marcus et al. 2003).
NTPDase2 (CD39L1), encoded by the ENTPD2 gene, is an ectonucleoside triphosphate diphosphohydrolase that is expressed at the plasma membrane where it hydrolyzes extracellular nucleoside triphosphates (ATP, GTP, CTP, ITP, UTP) to the respective nucleoside diphosphate (ADP, GDP, CDP, IDP, UDP) in the presence of Ca2+ of Mg2+ ions. NTPDase2 is only marginally active in hydrolyzing nucleoside diphosphates, such as ADP and UDP (Kegel et al. 1997, Kirley et al. 1997, Mateo et al. 1999). The alpha splicing isoform of NTPDase2 is expressed at the plasma membrane, while beta and gamma isoforms are expressed in the endoplasmic reticulum (Mateo et al. 2003). NTPDase2 may oligomerize and the oligomerization state may affect substrate specificity (Failer et al. 2003).
NTPDase3 (CD39L3), encoded by the ENTPD3 gene, is a plasma membrane-bound ectonucleotidase that hydrolyzes extracellular NTPs to NMPs via corresponding NDP intermediates (Smith and Kirley 1998, Lavoie et al. 2004, Kukulski et al. 2005). NTPDase3 is about 3 times more efficient in hydrolyzing ATP than ADP (Smith and Kirley 1998). NTPDase3 is expressed in some neurons (Belcher et al. 2006, Lavoie et al. 2010) where it may be involved in sleep-wake behaviour (Belcher et al. 2006). NTPDase3 is also expressed in islet cells where it may regulate insulin secretion (Lavoie et al. 2010).
NTPDase3 (CD39L3), encoded by the ENTPD3 gene, is a plasma membrane-bound ectonucleotidase that hydrolyzes extracellular NDPs to corresponding NMPs (Smith and Kirley 1998, Lavoie et al. 2004, Vorhoff et al. 2005, Kukulski et al. 2005).
NTPDase4 (UDPase), encoded by the ENTPD4 gene, belongs to the E-NTPDase family of nucleotide phosphatases. NTPDase4 localizes to the Golgi membrane, with active site on the Golgi lumen side. In the presence of Ca2+, NTPDase4 hydrolyzes nucleoside diphosphates UDP, GDP, CDP and dTDP to nucleoside monophosphates UMP, GMP, CMP and dTMP, respectively (Wang and Guidotti 1998).
NTPDase4 (UDPase), encoded by the ENTPD4 gene, is an E-NTPDase family member that localizes to the Golgi membrane and can hydrolyze nucleoside triphosphates UTP, GTP, CTP and TTP to nucleoside diphosphates UDP, GDP, CDP and TDP, respectively, in the Golgi lumen. NTPDase4 hydrolyzes nucleoside triphosphates less efficiently than nucleoside diphosphates. Ca2+ is needed for NTPDase4 activity (Wang and Guidotti 1998).
NTPDase5 (CD39L4), encoded by the ENTPD5 gene, is an E-NTPDase family member that is secreted to the extracellular space where it hydrolyzes nucleoside diphosphates UDP, GDP, CDP and ADP (listed in the order of preference) to nucleoside monophosphates UMP, GMP, CMP and AMP, respectively. In vitro, NTPDase5 can hydrolyze nucleoside triphosphates GTP, CTP, UTP and ATP to corresponding nucleoside diphosphates but with very low efficiency. NTPDase5 requires Ca2+ or Mg2+ for catalytic activity (Mulero et al. 1999). NTPDase5 is most catalytically active as a monomer, although it can also form disulfide-linked dimers (Mulero et al. 2000).
NTPDase5 may function in the endoplasmic reticulum (ER), where its UDPase activity could contribute to protein glycosylation and folding. NTPDase5 may alleviate ER stress induced by protein overload caused by oncogenic PI3K/AKT signaling in cancer cells. NTPDase5 is over-expressed in tumors with activated AKT and is known as the PCPH oncogene. The underlying mechanism of NTPDase5 over-expression may be AKT-mediated inhibition of FOXO proteins, which are probable transcriptional repressors of the ENTPD5 gene (Fang et al. 2010, Shen et al. 2011).
NTPDase6 (CD39L2), encoded by the ENTPD6 gene, is an ectonucleotide phosphatase of the E-NTPDase family that can be secreted (Yeung et al. 2000). Secretion involves the removal of the first 77 amino acids at the N-terminus by an unknown peptidase. Secreted NTPDase6 hydrolyzes nucleoside diphosphates GDP, IDP and, less efficiently, UDP and CDP to nucleoside monophosphates GMP, IMP, UMP and CMP, respectively. Secreted NTPDase6 hydrolyzes ADP to AMP and nucleoside triphosphates GTP, ITP, UTP and CTP to corresponding nucleoside diphosphates with very low efficacy (Hicks-Berger et al. 2000, Yeung et al. 2000, Ivanenkov et al. 2003). NTPDase6 requires Ca2+ or Mg2+ for catalytic activity (Hicks-Berger et al. 2000, Ivanenkov et al. 2003).
NTPDase6 may also be able to function as a membrane-bound enzyme, but its catalytic rate is very low and accounts for up to 10% of NTPDase6 activity (Hicks-Berger et al. 2000).
NTPDase7 (LALP1), encoded by the ENTPD7 gene, is a cytoplasmic vesicle membrane-bound nucleotide phosphatase that hydrolyzes nucleoside triphosphates CTP, GTP and UTP to nucleoside diphosphates CDP, GDP and UDP, respectively. NTPDase7 may have a low activity towards ATP and nucleoside diphosphates (Shi et al. 2001). NTPDase7 requires Ca2+ for catalytic activity (Shi et al. 2001). In mice, NTPDase7 was shown to regulate development of IL17-secreting Th17 cells in the small intestine, possibly by regulating extracellular ATP levels (Kusu et al. 2013).
NTPDase8, encoded by the ENTPD8 gene, is an E-NTPDase family ectonucleotide phosphatase that, in the presence of Ca2+ or Mg2+, hydrolyzes NTPs to NMPs, via corresponding NDP intermediates. NTPDase8 is more efficient in hydrolyzing NTPs than NDPs. NTPDase8 provides the main ectonucleotide phosphatase activity in rat and porcine livers (Sevigny et al. 2000, Fausther et al. 2007).
SAMHD1:Zn2+ tetramer (Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, also known as SAM domain and HD domain-containing protein 1) catalyzes the hydrolysis of dNTPs (2'-deoxynucleoside 5'-triphosphates) to form 2'-deoxynucleosides and PPPi (triphosphate) (Goldstone et al. 2011; Powell et al. 2011). The active form of the enzyme is a tetramer with one Zn2+ ion associated with each monomer subunit (Yan et al. 2013; Zhu et al. 2013) localized in the nucleus (Franzolin et al. 2013; Rice et al. 2009). The enzyme is activated by dGTP (Powell et al. 2011).
SAMHD1 activity may play a role in regulating the size of the nuclear pools of dNTPs and dissipating these pools at the end of the S phase of the cell cycle (Franzolin et al. 2013) and it may play a role as well in regulating cellular antiviral responses (Goldstone et al. 2011; Rice et al. 2009).
2'-deoxynucleoside 5'-phosphate N-hydrolase 1 (DNPH1 aka c-Myc-responsive protein RCL) is a cytosolic protein which catalyses the cleavage of the N-glycosidic bond of deoxyribonucleoside 5'-monophosphates to yield deoxyribose 5-phosphate (2DORP) and a purine or pyrimidine base. Of the six 2'-deoxynucleoside 5'-monophosphates, DNPH1 has highest affinity for the purine deoxynucleotide dGMP (Amiable et al. 2013). The same affinity for purine deoxynucleotides over pyrimidine deoxynucleotides was observed for rat Dnph1 (Ghiorghi et al. 2007). DNPH1 is a potential target for anti-cancer therapies (Amiable et al. 2014) as it is involved in cellular proliferation and is up-regulated in several types of cancer.
The mitochondrial uptake of cytosolic (R)-3-aminoisobutyric acid in human cells is inferred from the corresponding process known to occur in rat (Tamaki et al. 2000).
The mitochondrial uptake of cytosolic beta-alanine in human cells is inferred from the corresponding process known to occur in rat (Tamaki et al. 2000).
Mitochondrial AGXT2 tetramer catalyzes the reaction of beta-alanine and pyruvate to form 3-oxopropanoate and alanine. While the human mitochondrial AGXT2 enzyme has been characterized experimentally in other respects (Rodionov et al. 2010), its ability to catalyze this transamination reaction is inferred from the properties of its rat homologue.
Mitochondrial AGXT2 tetramer catalyzes the reaction of (R)-3-aminoisobutyric acid and pyruvate to form 2-methyl-3-oxopropanoate and alanine. While the human mitochondrial AGXT2 enzyme has been characterized experimentally in other respects (Rodionov et al. 2010), its ability to catalyze this transamination reaction is inferred from the properties of its rat homologue.
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Together, these data support the hypothesis that by cleaving 2-hydroxy-dATP and thus preventing its incorporation into DNA, NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress. This hypothesis is further supported by the demonstration that mice lacking NUDT1 show an increased lifetime incidence of liver and other tumors compared to normal controls, and that rapidly metabolizing tumor cells in culture are killed under conditions where synthesis of NUDT1 protein is suppressed or its catalytic activity is inhibited (Gad et al. 2014; Huber et al. 2014).
Together, these data support the hypothesis that by cleaving 8-oxo-dGTP and thus preventing its incorporation into DNA NUDT1 provides a physiologically important defense against mutagenesis due to oxidative stress. This hypothesis is further supported by the demonstration that mice lacking NUDT1 show an increased lifetime incidence of liver and other tumors compared to normal controls, and that rapidly metabolizing tumor cells in culture are killed under conditions where synthesis of NUDT1 protein is suppressed or its catalytic activity is inhibited (Gad et al. 2014; Huber et al. 2014).
NTPDase2 may contribute to vascular hemostasis by exerting an opposing role to NTPDase1 (Sévigny et al. 2002).
NTPDase5 may function in the endoplasmic reticulum (ER), where its UDPase activity could contribute to protein glycosylation and folding. NTPDase5 may alleviate ER stress induced by protein overload caused by oncogenic PI3K/AKT signaling in cancer cells. NTPDase5 is over-expressed in tumors with activated AKT and is known as the PCPH oncogene. The underlying mechanism of NTPDase5 over-expression may be AKT-mediated inhibition of FOXO proteins, which are probable transcriptional repressors of the ENTPD5 gene (Fang et al. 2010, Shen et al. 2011).
NTPDase6 may also be able to function as a membrane-bound enzyme, but its catalytic rate is very low and accounts for up to 10% of NTPDase6 activity (Hicks-Berger et al. 2000).
SAMHD1 activity may play a role in regulating the size of the nuclear pools of dNTPs and dissipating these pools at the end of the S phase of the cell cycle (Franzolin et al. 2013) and it may play a role as well in regulating cellular antiviral responses (Goldstone et al. 2011; Rice et al. 2009).