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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
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MetaCyc Pathway: pyrimidine deoxyribonucleosides salvage

Enzyme View:

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Nucleosides and Nucleotides Biosynthesis Pyrimidine Nucleotide Biosynthesis Pyrimidine Nucleotides Salvage

Some taxa known to possess this pathway include ? : Arabidopsis thaliana col , Bacillus anthracis , Bacillus subtilis subtilis 168 , Glycine max , Homo sapiens , Mycobacterium tuberculosis H37Rv , Pisum sativum

Expected Taxonomic Range: Amoebozoa , Archaea , Bacteria , Metazoa , Viridiplantae

Summary:
General Background

Deoxyribonucleotides are synthesised de novo at the diphosphate level through reduction of the 2'-hydroxyl group of the corresponding ribonucleotides (see pyrimidine deoxyribonucleotides de novo biosynthesis I). This reduction is mediated by the key enzyme ribonucleoside-diphosphate reductase.

The de novo synthesis of ribonucleotides is very expensive, and organisms have adapted to salvage potential precursors from their environment. Since nucleotides can not be imported into the cell due to the negative charge of the phosphate groups, salvage is limited to free bases and nucleosides.

Salvage is very important for many types of organisms and cells. It has been shown that in quiescent or terminally differentiated mammalian cells, resting in the G0 phase, ribonucleotide reductase is not produced due to a block during transcription and the cells rely on salvage for deoxyribonucleotides for DNA repair [Mann88, Bjorklund90]. Similarly, the salvage pathway is the sole provider of deoxyribonucleotides to be used in DNA repair or mitochondrial DNA replication in G1 cells. Studies with the plant Arabidopsis thaliana showed that uracil salvage is necessary for early development [Mainguet09] and that uridine salvage plays a crucial role in photoassimilate allocation and partioning [Chen11].

The deoxyribonucleosides enter through the cell membrane by facilitated diffusion via a low affinity, high capacity, non-concentrative nucleoside carrier protein with a wide specificity, possessed by almost all animal cells [Plagemann88]. The next step in the salvage pathway is the phosphorylation of the nucleosides to monophosphates. Once phosphorylation occurs, the nucleotides are trapped intracellularly due to their negative charge.

About This Pathway

Deoxyribonucleoside kinases salvage deoxyribonucleosides by phosphorylating them at the 5' position. The key enzymes in the salvage of pyrimidine deoxyribonucleosides are thymidine kinase (EC 2.7.1.21) (which also phosphorylates deoxyuridine) and deoxycytidine kinase (EC 2.7.1.74). This salvage pathway is well characterized in bacteria [Rima77], mammals [Arner95], and plants [Clausen12].

Mammalian cells contain both of these kinases. In humans deoxycytidine kinase is encoded by the DCK gene, while two isozymes, encoded by TK1 and TK2, catalyze thymidine kinase activity [Hershfield82, Cory93].

Arabidopsis thaliana posseses two thymidine kinase genes (TK1a and TK1b), and a broad substrate range deoxynucleoside kinase encoded by a single DNK gene that can phosphorylate both 2'-deoxyuridine and 2'-deoxycytidine [Clausen12].

Most eubacteria also employ this salvage pathway. However, some organisms, including Escherichia coli and Salmonella enterica enterica serovar Typhi, lack the enzyme that phosphorylates deoxycytidine [ECOSAL]. The yeast Saccharomyces cerevisiae does not have any deoxyribonucleoside kinases, and thus does not possess this pathway.

In addition to these two kinases, the pathway also shows how 2'-deoxycytidine can be salvaged for the synthesis of deoxythymidine nucleotides. This is enabled by deamination to 2'-deoxyuridine, followed by phosphorylation by thymidine kinase to form dUMP. The latter can be converted directly to dTMP by the action of thymidylate synthase (EC 2.1.1.45).

Superpathways: superpathway of pyrimidine deoxyribonucleoside salvage

Credits:
Created 09-Dec-2002 by Arnaud M , SRI International
Revised 14-Jul-2006 by Ingraham JL , UC Davis
Revised 29-Jan-2013 by Caspi R , SRI International


References

Arner95: Arner ES, Eriksson S (1995). "Mammalian deoxyribonucleoside kinases." Pharmacol Ther 67(2);155-86. PMID: 7494863

Bjorklund90: Bjorklund S, Skog S, Tribukait B, Thelander L (1990). "S-phase-specific expression of mammalian ribonucleotide reductase R1 and R2 subunit mRNAs." Biochemistry 29(23);5452-8. PMID: 1696835

Chen11: Chen M, Thelen JJ (2011). "Plastid uridine salvage activity is required for photoassimilate allocation and partitioning in Arabidopsis." Plant Cell 23(8);2991-3006. PMID: 21828290

Clausen12: Clausen AR, Girandon L, Ali A, Knecht W, Rozpedowska E, Sandrini MP, Andreasson E, Munch-Petersen B, Piškur J (2012). "Two thymidine kinases and one multisubstrate deoxyribonucleoside kinase salvage DNA precursors in Arabidopsis thaliana." FEBS J 279(20);3889-97. PMID: 22897443

Cory93: Cory AH, Shibley IA, Chalovich JM, Cory JG (1993). "Deoxyguanosine-resistant leukemia L1210 cells. Loss of specific deoxyribonucleoside kinase activity." J Biol Chem 268(1);405-9. PMID: 8380161

ECOSAL: EcoSal "Escherichia coli and Salmonella: Cellular and Molecular Biology." Online edition.

Hershfield82: Hershfield MS, Fetter JE, Small WC, Bagnara AS, Williams SR, Ullman B, Martin DW, Wasson DB, Carson DA (1982). "Effects of mutational loss of adenosine kinase and deoxycytidine kinase on deoxyATP accumulation and deoxyadenosine toxicity in cultured CEM human T-lymphoblastoid cells." J Biol Chem 257(11);6380-6. PMID: 6281270

Mainguet09: Mainguet SE, Gakiere B, Majira A, Pelletier S, Bringel F, Guerard F, Caboche M, Berthome R, Renou JP (2009). "Uracil salvage is necessary for early Arabidopsis development." Plant J 60(2);280-91. PMID: 19563437

Mann88: Mann GJ, Musgrove EA, Fox RM, Thelander L (1988). "Ribonucleotide reductase M1 subunit in cellular proliferation, quiescence, and differentiation." Cancer Res 48(18);5151-6. PMID: 3044582

Plagemann88: Plagemann PG, Wohlhueter RM, Woffendin C (1988). "Nucleoside and nucleobase transport in animal cells." Biochim Biophys Acta 947(3);405-43. PMID: 3048401

Rima77: Rima BK, Takahashi I (1977). "Metabolism of pyrimidine bases and nucleosides in Bacillus subtilis." J Bacteriol 129(2);574-9. PMID: 402352

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Andersen01: Andersen RB, Neuhard J (2001). "Deoxynucleoside kinases encoded by the yaaG and yaaF genes of Bacillus subtilis. Substrate specificity and kinetic analysis of deoxyguanosine kinase with UTP as the preferred phosphate donor." J Biol Chem 276(8);5518-24. PMID: 11078735

Anderson11: Anderson DD, Quintero CM, Stover PJ (2011). "Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria." Proc Natl Acad Sci U S A 108(37);15163-8. PMID: 21876188

Ashley84: Ashley GW, Bartlett PA (1984). "Purification and properties of cytidine deaminase from escherichia coli." J Biol Chem 1984;259(21);13615-20. PMID: 6386817

Bello74: Bello LJ (1974). "Regulation of thymidine kinase synthesis in human cells." Exp Cell Res 89(2);263-74. PMID: 4457349

Bradshaw83: Bradshaw HD (1983). "Molecular cloning and cell cycle-specific regulation of a functional human thymidine kinase gene." Proc Natl Acad Sci U S A 80(18);5588-91. PMID: 6577446

Bradshaw84: Bradshaw HD, Deininger PL (1984). "Human thymidine kinase gene: molecular cloning and nucleotide sequence of a cDNA expressible in mammalian cells." Mol Cell Biol 4(11);2316-20. PMID: 6549046

BRENDA14: BRENDA team (2014). "Imported from BRENDA version existing on Aug 2014." http://www.brenda-enzymes.org.

Brent71: Brent TP (1971). "Periodicity of DNA synthetic enzymes during the HeLa cell cycle." Cell Tissue Kinet 4(4);297-305. PMID: 5316024

Carnrot06: Carnrot C, Vogel SR, Byun Y, Wang L, Tjarks W, Eriksson S, Phipps AJ (2006). "Evaluation of Bacillus anthracis thymidine kinase as a potential target for the development of antibacterial nucleoside analogs." Biol Chem 387(12);1575-81. PMID: 17132103

Chen78: Chen MS, Prusoff WH (1978). "Thymidine kinase from Escherichia coli." Methods Enzymol 1978;51;354-60. PMID: 357898

Chottiner91: Chottiner EG, Shewach DS, Datta NS, Ashcraft E, Gribbin D, Ginsburg D, Fox IH, Mitchell BS (1991). "Cloning and expression of human deoxycytidine kinase cDNA." Proc Natl Acad Sci U S A 88(4);1531-5. PMID: 1996353

Chung05: Chung SJ, Fromme JC, Verdine GL (2005). "Structure of human cytidine deaminase bound to a potent inhibitor." J Med Chem 48(3);658-60. PMID: 15689149

Clausen08: Clausen AR, Girandon L, Knecht W, Survery S, Andreasson E, Munch-Petersen B, Piskur J (2008). "A multisubstrate deoxyribonucleoside kinase from plants." Nucleic Acids Symp Ser (Oxf) (52);489-90. PMID: 18776467

Davisson89: Davisson VJ, Sirawaraporn W, Santi DV (1989). "Expression of human thymidylate synthase in Escherichia coli." J Biol Chem 264(16);9145-8. PMID: 2656695

Demontis98: Demontis S, Terao M, Brivio M, Zanotta S, Bruschi M, Garattini E (1998). "Isolation and characterization of the gene coding for human cytidine deaminase." Biochim Biophys Acta 1443(3);323-33. PMID: 9878810

Elsevier74: Elsevier SM, Kucherlapati RS, Nichols EA, Creagan RP, Giles RE, Ruddle FH, Willecke K, McDougall JK (1974). "Assignment of the gene for galactokinase to human chromosome 17 and its regional localisation to band q21-22." Nature 251(5476);633-6. PMID: 4371022

Eriksson91: Eriksson S, Kierdaszuk B, Munch-Petersen B, Oberg B, Johansson NG (1991). "Comparison of the substrate specificities of human thymidine kinase 1 and 2 and deoxycytidine kinase toward antiviral and cytostatic nucleoside analogs." Biochem Biophys Res Commun 176(2);586-92. PMID: 2025274

Eriksson91a: Eriksson S, Cederlund E, Bergman T, Jornvall H, Bohman C (1991). "Characterization of human deoxycytidine kinase. Correlation with cDNA sequences." FEBS Lett 280(2);363-6. PMID: 2013338

FaivreNitschke99: Faivre-Nitschke SE, Grienenberger JM, Gualberto JM (1999). "A prokaryotic-type cytidine deaminase from Arabidopsis thaliana gene expression and functional characterization." Eur J Biochem 263(3);896-903. PMID: 10469156

Flemington87: Flemington E, Bradshaw HD, Traina-Dorge V, Slagel V, Deininger PL (1987). "Sequence, structure and promoter characterization of the human thymidine kinase gene." Gene 52(2-3);267-77. PMID: 3301530

Showing only 20 references. To show more, press the button "Show all references".


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sat Dec 20, 2014, biocyc14.