Nucleosides and free bases generated by RNA and DNA breakdown are converted back to nucleotide monophosphates, allowing them to re-enter the pathways of nucleotide biosynthesis and interconversion. Under normal conditions, DNA turnover is limited and deoxyribonucleotide salvage operates at a correspondingly low level (Watts 1974).
View original pathway at Reactome.
Suzuki NN, Koizumi K, Fukushima M, Matsuda A, Inagaki F.; ''Structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase.''; PubMedEurope PMCScholia
Kashuba E, Kashuba V, Sandalova T, Klein G, Szekely L.; ''Epstein-Barr virus encoded nuclear protein EBNA-3 binds a novel human uridine kinase/uracil phosphoribosyltransferase.''; PubMedEurope PMCScholia
Hershfield MS, Fetter JE, Small WC, Bagnara AS, Williams SR, Ullman B, Martin DW, Wasson DB, Carson DA.; ''Effects of mutational loss of adenosine kinase and deoxycytidine kinase on deoxyATP accumulation and deoxyadenosine toxicity in cultured CEM human T-lymphoblastoid cells.''; PubMedEurope PMCScholia
Usova EV, Eriksson S.; ''Identification of residues involved in the substrate specificity of human and murine dCK.''; PubMedEurope PMCScholia
Norman RA, Barry ST, Bate M, Breed J, Colls JG, Ernill RJ, Luke RW, Minshull CA, McAlister MS, McCall EJ, McMiken HH, Paterson DS, Timms D, Tucker JA, Pauptit RA.; ''Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor.''; PubMedEurope PMCScholia
Roosild TP, Castronovo S, Fabbiani M, Pizzorno G.; ''Implications of the structure of human uridine phosphorylase 1 on the development of novel inhibitors for improving the therapeutic window of fluoropyrimidine chemotherapy.''; PubMedEurope PMCScholia
Birringer MS, Claus MT, Folkers G, Kloer DP, Schulz GE, Scapozza L.; ''Structure of a type II thymidine kinase with bound dTTP.''; PubMedEurope PMCScholia
Watts RW.; ''Molecular variation in relation to purine metabolism.''; PubMedEurope PMCScholia
Sherley JL, Kelly TJ.; ''Human cytosolic thymidine kinase. Purification and physical characterization of the enzyme from HeLa cells.''; PubMedEurope PMCScholia
Jansson O, Bohman C, Munch-Petersen B, Eriksson S.; ''Mammalian thymidine kinase 2. Direct photoaffinity labeling with [32P]dTTP of the enzyme from spleen, liver, heart and brain.''; PubMedEurope PMCScholia
Wang L, Munch-Petersen B, Herrström Sjöberg A, Hellman U, Bergman T, Jörnvall H, Eriksson S.; ''Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates.''; PubMedEurope PMCScholia
Datta NS, Shewach DS, Mitchell BS, Fox IH.; ''Kinetic properties and inhibition of human T lymphoblast deoxycytidine kinase.''; PubMedEurope PMCScholia
Andres CM, Fox IH.; ''Purification and properties of human placental adenosine kinase.''; PubMedEurope PMCScholia
Mathews II, Erion MD, Ealick SE.; ''Structure of human adenosine kinase at 1.5 A resolution.''; PubMedEurope PMCScholia
Hurley MC, Lin B, Fox IH.; ''Regulation of deoxyadenosine and nucleoside analog phosphorylation by human placental adenosine kinase.''; PubMedEurope PMCScholia
Johansson K, Ramaswamy S, Ljungcrantz C, Knecht W, Piskur J, Munch-Petersen B, Eriksson S, Eklund H.; ''Structural basis for substrate specificities of cellular deoxyribonucleoside kinases.''; PubMedEurope PMCScholia
Park I, Ives DH.; ''Properties of a highly purified mitochondrial deoxyguanosine kinase.''; PubMedEurope PMCScholia
Johansson M, Karlsson A.; ''Cloning and expression of human deoxyguanosine kinase cDNA.''; PubMedEurope PMCScholia
Ealick SE, Rule SA, Carter DC, Greenhough TJ, Babu YS, Cook WJ, Habash J, Helliwell JR, Stoeckler JD, Parks RE.; ''Three-dimensional structure of human erythrocytic purine nucleoside phosphorylase at 3.2 A resolution.''; PubMedEurope PMCScholia
Jolly DJ, Okayama H, Berg P, Esty AC, Filpula D, Bohlen P, Johnson GG, Shively JE, Hunkapillar T, Friedmann T.; ''Isolation and characterization of a full-length expressible cDNA for human hypoxanthine phosphoribosyl transferase.''; PubMedEurope PMCScholia
Mahnke-Zizelman DK, Tullson PC, Sabina RL.; ''Novel aspects of tetramer assembly and N-terminal domain structure and function are revealed by recombinant expression of human AMP deaminase isoforms.''; PubMedEurope PMCScholia
Sherley JL, Kelly TJ.; ''Regulation of human thymidine kinase during the cell cycle.''; PubMedEurope PMCScholia
Munch-Petersen B, Cloos L, Tyrsted G, Eriksson S.; ''Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides.''; PubMedEurope PMCScholia
Watanabe S, Uchida T.; ''Cloning and expression of human uridine phosphorylase.''; PubMedEurope PMCScholia
Greenberg N, Schumm DE, Webb TE.; ''Uridine kinase activities and pyrimidine nucleoside phosphorylation in fluoropyrimidine-sensitive and -resistant cell lines of the Novikoff hepatoma.''; PubMedEurope PMCScholia
Desgranges C, Razaka G, Rabaud M, Bricaud H.; ''Catabolism of thymidine in human blood platelets: purification and properties of thymidine phosphorylase.''; PubMedEurope PMCScholia
Williams SR, Gekeler V, McIvor RS, Martin DW.; ''A human purine nucleoside phosphorylase deficiency caused by a single base change.''; PubMedEurope PMCScholia
Datta NS, Shewach DS, Hurley MC, Mitchell BS, Fox IH.; ''Human T-lymphoblast deoxycytidine kinase: purification and properties.''; PubMedEurope PMCScholia
Chung SJ, Fromme JC, Verdine GL.; ''Structure of human cytidine deaminase bound to a potent inhibitor.''; PubMedEurope PMCScholia
Wang L, Hellman U, Eriksson S.; ''Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA.''; PubMedEurope PMCScholia
Hatzis P, Al-Madhoon AS, Jüllig M, Petrakis TG, Eriksson S, Talianidis I.; ''The intracellular localization of deoxycytidine kinase.''; PubMedEurope PMCScholia
Van Rompay AR, Johansson M, Karlsson A.; ''Substrate specificity and phosphorylation of antiviral and anticancer nucleoside analogues by human deoxyribonucleoside kinases and ribonucleoside kinases.''; PubMedEurope PMCScholia
Munch-Petersen B, Tyrsted G, Cloos L.; ''Reversible ATP-dependent transition between two forms of human cytosolic thymidine kinase with different enzymatic properties.''; PubMedEurope PMCScholia
Bausch-Jurken MT, Mahnke-Zizelman DK, Morisaki T, Sabina RL.; ''Molecular cloning of AMP deaminase isoform L. Sequence and bacterial expression of human AMPD2 cDNA.''; PubMedEurope PMCScholia
Preumont A, Rzem R, Vertommen D, Van Schaftingen E.; ''HDHD1, which is often deleted in X-linked ichthyosis, encodes a pseudouridine-5'-phosphatase.''; PubMedEurope PMCScholia
Chottiner EG, Shewach DS, Datta NS, Ashcraft E, Gribbin D, Ginsburg D, Fox IH, Mitchell BS.; ''Cloning and expression of human deoxycytidine kinase cDNA.''; PubMedEurope PMCScholia
Shewach DS, Reynolds KK, Hertel L.; ''Nucleotide specificity of human deoxycytidine kinase.''; PubMedEurope PMCScholia
Bohman C, Eriksson S.; ''Deoxycytidine kinase from human leukemic spleen: preparation and characteristics of homogeneous enzyme.''; PubMedEurope PMCScholia
LEE YP.; ''5'-Adenylic acid deaminase. III. Properties and kinetic studies.''; PubMedEurope PMCScholia
Murakami E, Bao H, Mosley RT, Du J, Sofia MJ, Furman PA.; ''Adenosine deaminase-like protein 1 (ADAL1): characterization and substrate specificity in the hydrolysis of N(6)- or O(6)-substituted purine or 2-aminopurine nucleoside monophosphates.''; PubMedEurope PMCScholia
Sabini E, Ort S, Monnerjahn C, Konrad M, Lavie A.; ''Structure of human dCK suggests strategies to improve anticancer and antiviral therapy.''; PubMedEurope PMCScholia
Wiginton DA, Coleman MS, Hutton JJ.; ''Characterization of purine nucleoside phosphorylase from human granulocytes and its metabolism of deoxyribonucleosides.''; PubMedEurope PMCScholia
Akeson AL, Wiginton DA, Dusing MR, States JC, Hutton JJ.; ''Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts.''; PubMedEurope PMCScholia
Li J, Wei Z, Zheng M, Gu X, Deng Y, Qiu R, Chen F, Ji C, Gong W, Xie Y, Mao Y.; ''Crystal structure of human guanosine monophosphate reductase 2 (GMPR2) in complex with GMP.''; PubMedEurope PMCScholia
Lee LS, Cheng YC.; ''Human deoxythymidine kinase. I. Purification and general properties of the cytoplasmic and mitochondrial isozymes derived from blast cells of acute myelocytic leukemia.''; PubMedEurope PMCScholia
Sarup JC, Johnson MA, Verhoef V, Fridland A.; ''Regulation of purine deoxynucleoside phosphorylation by deoxycytidine kinase from human leukemic blast cells.''; PubMedEurope PMCScholia
Ashby B, Frieden C.; ''Adenylate deaminase. Kinetic and binding studies on the rabbit muscle enzyme.''; PubMedEurope PMCScholia
Deng Y, Wang Z, Ying K, Gu S, Ji C, Huang Y, Gu X, Wang Y, Xu Y, Li Y, Xie Y, Mao Y.; ''NADPH-dependent GMP reductase isoenzyme of human (GMPR2). Expression, purification, and kinetic properties.''; PubMedEurope PMCScholia
Johansson M.; ''Identification of a novel human uridine phosphorylase.''; PubMedEurope PMCScholia
Spector T, Jones TE, Miller RL.; ''Reaction mechanism and specificity of human GMP reductase. Substrates, inhibitors, activators, and inactivators.''; PubMedEurope PMCScholia
Cytosolic adenosine kinase (ADK) catalyzes the reactions of adenosine and deoxyadenosine with ATP to yield the corresponding nucleotide monophosphates and ADP (Andres and Fox 1979). The enzyme is substantially more active on adenosine than deoxyadenosine in vitro (Hurley at al. 1985) though studies of cultured cells suggest that both reactions may be physiologically relevant (Hershfield et al. 1982). The enzyme is a monomer complexed with magnesium (Mathews et al. 1998).
Cytosolic deoxycytidine kinase (DCK) catalyzes the reactions of deoxyadenosine and deoxyguanosine with ATP to form the corresponding nucleotide monophosphates and AMP, The enzyme is a dimer (Bohman and Eriksson 1988; Datta et al. 1989). While the enzyme can be found in nuclei of cultured cells expressing high levels of a tagged recombinant protein, its normal location appears to be cytosolic (Hatzis et al. 1998).
Mitochondrial thymidine kinase 2 (TK2) catalyzes the reactions of deoxycytidine, thymidine, and deoxyuridine with ATP to form the corresponding deoxynucleotide monophosphates and ADP. The enzyme has been purified from human spleen and is active as a monomer (Munch-Petersen et al. 1991). The enzyme requires divalent cations for activity (Mg++ is preferred) but the nature of the association between the metal ion and the enzyme polypeptide is unclear (Lee and Cheng 1976). The mitochondrial localization of the enzyme has been established experimentally for rats and cattle (Jansson et al. 1992); its mitochondrial localization in humans is inferred from these results and the presence of a mitochondrial localization motif at the amino terminus of the open reading frame of a cloned human cDNA that is missing from the mature catalytically active protein (Wang et al. 1999).
Cytosolic uridine-cytidine kinase 2 (UCK2) catalyzes the reactions of cytidine or uridine with ATP to form CMP or UMP and ADP (Greenberg et al. 1977; Van Rompay et al. 2001). Crystallographic data show the enzyme to be a tetramer (Suzuki et al. 2004). When it is expressed as a fusion construct with green fluorescent protein, the protein localizes primarily to the cytosol of transfected CHO cells (Van Rompay et al. 2003).
Cytosolic nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of hypoxanthine with ribose 1-phosphate or deoxyribose 1-phosphate to form inosine or deoxyinosine and orthophosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either ribose 1-phosphate or deoxyribose 1-phosphate in vitro, levels of deoxyribose 1-phosphate 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 nucleoside phosphorylase (NP) trimer catalyzes the reversible reaction of guanine with ribose 1-phosphate or deoxyribose 1-phosphate to form guanosine or deoxyguanosine and orthophosphate (Ealick et al. 1990; Wiginton et al. 1980). While NP is active with either ribose 1-phosphate or deoxyribose 1-phosphate in vitro, levels of deoxyribose 1-phosphate 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 thymidine phosphorylase (TYMP) catalyzes the reversible reactions of thymine or uracil with 2-deoxy-D-ribose 1-phosphate to form thymidine or deoxyuridine and orthiophosphate. The active form of the enzyme is a homodimer (Desgranges et al. 1981; Norman et al. 2004; Usuki et al. 1992).
Cytosolic ADAL (Adenosine DeAminase-Like) catalyzes the reaction of N6-methyl-AMP and water to form IMP and methylamine. The active form of the enzyme is a protein monomer complexed with a zinc ion (Murakami et al. 2011).
Cytosolic GMP reductase (GMPR) catalyzes the reaction of GMP and NADPH + H+ to yield IMP and NADP+ + NH4+ (Spector et al. 1979; Deng et al. 2002). Two GMPR proteins have been identified, GMPR and GMPR2. Both proteins form homotetramers (GMPR - unpublished crstallographic data PDB 2BLE; GMPR2 - Li et al. 2006).
Pseudouridine 5'-phosphate (PURIDP) is a potential intermediate in RNA degradation. Pseudouridine 5'-phosphatase (HDHD1) is a Mg2+-dependent enzyme present in erythrocytes that can dephosphorylate PURIDP to pseudouridine (PURID), the fifth-most abundant nucleoside in RNA. PURID is not metabolised in mammals but excreted intact in urine (Preumont et al. 2010).
Cytosolic deoxycytidine kinase (DCK) catalyzes the reactions of cytidine or deoxycytidine with ATP to form CMP or dCMP and ADP. The enzyme is a homodimer (Sabini et al. 2003). Although a chimeric deoxycytidine kinase - green fluorescent protein expressed at high levels in cultured cells localized to nuclei, endogenous protein is primarily cytosolic (Hatzis et al. 1998). Despite its name, the enzyme has a broad substrate specificity, acting on cytidine, deoxycytidine, deoxyguanosine, and deoxyadenosine (Bohman and Eriksson 1988; Datta et al. 1989a, b; Sarup et al. 1989; Usova and Eriksson 2002). While ATP functions efficiently as a phosphate donor, other nucleoside triphosphates, notably UTP, function efficiently as phosphate donors in vitro and may function in this way in vivo as well (Shewach et al. 1992).
Cytosolic uridine-cytidine kinase 1 (UCK1) catalyzes the reactions of cytidine or uridine with ATP to form CMP or UMP and ADP (Greenberg et al. 1977; Van Rompay et al. 2001). Unpublished crystallographic data show the enzyme to be a tetramer (PDB - 2JEO).
Cytosolic cytidine deaminase catalyzes the hydrolysis of cytidine or dexoycytidine to form uridine or deoxyuridine and ammonia (Laliberte and Momparler 1994). The active form of the enzyme is a tetramer (Chung et al. 2005).
Cytosolic thymidine kinase 1 (TK1) catalyzes the reaction of thymidine and ATP to form TMP (thymidine 5'-monophosphate) and ADP. TK1 has been purified from human spleen and from cultured cells. The enzyme is active as a homotetramer, and phosphorylates thymidine and deoxyuridine using ATP as a phosphate donor in vitro (Sherley and Kelly 1988a; Munch-Petersen et al. 1991; Birringer et al. 2005). Divalent cations are required for enzyme activity (Mg++ is preferred) (Lee and Cheng 1986), and ATP stabilizes the tetrameric form of the enzyme (Munch-Petersen et al. 1993). In cells, enzyme activity is high during S phase of the cell cycle and low otherwise, correlated with intracellular levels of thymidine kinase 1 protein (Sherley and Kelly 1988b), and consistent with a requirement for TMP synthesis in normal cells only as part of DNA replication.
Mitochondrial deoxyguanosine kinase (DGUOK) catalyzes the reactions of deoxyadenosine, deoxyguanosine, and deoxyinosine with ATP to form the corresponding nucleotide monophosphates and ADP (Park and Ives 1988; Johansson and Karlson 1996). Crystallographic studies of the human enzyme have confirmed its dimeric structure and allowed identification of key amino acid residues responsible for its substrate specificity (Johansson et al. 2001).
Cytosolic hypoxanthine-guanine phosphoribosyltransferase (HPRT1) tetramer catalyzes the reactions of guanine or hypoxanthine with PRPP to form GMP ir IMP and pyrophosphate (Holden and Kelley 1978; Jolly et al. 1983).
Cytosolic adenosine deaminase (ADA) catalyzes the hydrolysis of 2'deoxyadenosine and adenosine to yield deoxyinosine and inosine, respectively, plus ammonia (Akeson et al. 1988). Unpublished crystallographic data (PDB 3IAR) indicate that the human enzyme is a monomer.
Cytosolic uridine phosphorylase (isoforms UPP1 and UPP2) catalyzes the reversible reactions of uracil with ribose 1-phosphate or deoxyribose 1-phosphate to yield uridine or deoxyuridine and orthophosphate (Watanabe and Uchida 1995; Johansson, 2003). The active form of UPP1 is a dimer (Rooslid et al. 2009).
Cytosolic AMP deaminase (AMPD) catalyzes the hydrolysis of AMP to yield IMP and ammonia. Three isoforms of AMPD, E, L, and M, have been identified that differ in their expression patterns in the body. All occur as tetramers and all have qualitatively the same catalytic activity, however (Bausch-Jurken et al. 1992; Mahnke-Zizelman et al. 1998).
Based on sequence similarity, cytosolic uridine-cytidine kinase-like 1 (UCKL1 aka F538) is thought to function as a novel human uridine kinase/uracil phosphoribosyltransferase (Kashuba et al. 2002). The two human uridine kinases 1 and 2 (UCK1 and UCK2) characterised to date phosphorylate uridine/cytidine to uridine monophosphate (UMP)/cytidine monophosphate (CMP) using ATP as a phosphate donor (Greenberg et al. 1977, Van Rompay et al. 2001).
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