MetaCyc Pathway: oxidized GTP and dGTP detoxification
Inferred from experiment

Enzyme View:

Pathway diagram: oxidized GTP and dGTP detoxification

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.

Synonyms: 8-oxo-(d)GTP detoxification, oxidized guanosine triphosphate and deoxyguanosine triphosphate detoxification, 8-oxo-7,8-dihydro-guanosine-triphosphate and 8-oxo-7,8-dihydro-deoxyguanosine-triphosphate

Superclasses: Detoxification
Metabolic Clusters

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Escherichia coli, Homo sapiens, Saccharomyces cerevisiae

Expected Taxonomic Range: Bacteria , Opisthokonta, Viridiplantae

General background

Maintenance of genomic and transcriptomic integrity is a vital goal of all organisms. Cells are often subjected to reactive oxygen species (ROS), such as hydroxyl radical, that can arise from due to oxidative stress, ionizing radiation, and certain aspects of normal cellular metabolism. These ROS can modify nucletide bases and cause problems during DNA replication and RNA transcription. This damage can occur on free nucleotides or in the context of DNA or RNA macromolecules. Organisms have evolved several strategies for trying to combat the damage that can be caused by oxidative stress, including this pathway that is involved in eliminating a source of potentially mutagenic nucleotides before they can be used for DNA replication or mRNA transcription [Rogacheva08].

Oxidation of the free GTP and dGTP can occur spontaneously in cells when a hydroxyl radical attacks the C8 position of the purine base guanine [Haghdoost06]. If the 8-oxo-dGTP is incorporated into DNA, it can pair with a C or an A and lead to G:C ->T:A or A:T -> C:G transversions respectively, although the A:T to C:G transversion seems to be more common in vivo ( [Maki92, Rogacheva08]). Similarly, an 8-oxo-GTP can be incorrectly incorporated opposite an adenosine residue during RNA transcription [Yoshimura07]. To prevent these errors, a Nudix hydrolase acts to remove a pyrophophate group from the oxidized nucelotides, thus, rendering them incompetent for incorporation into DNA or RNA [Rogacheva08]. It is important to note that there is evidence from humans that 8-oxo-dGMP cannot be re-phosphorylated by the guanylate kinase enzyme [Hayakawa95].

Oxidized (d)GTP appears to be a potentially major source of genetic lesions. Both mutant E.coli and eukaryotes show marked increases in DNA and RNA errors when this pathway is blocked . And the errors caused by the failure of this pathway may be linked to cancer and other DNA-damage related diseases [Maki92, Yoshimura07, Rogacheva08].

About this pathway

The ROS-induced steps shown in this pathway occur spontaneously. The subsequent de-toxification of the damaged free nucleotides is carried out by the members of the Nudix family of hydrolases. MutT from E.coli was the first characterized protein shown to have this protective pyrophosphatase activity [Taddei97]. Homologs of this protein have been functionally characterized in species as distantly related as humans [Mo92], the yeast S. cerevisiae [Nunoshiba04] , and Arabidopsis plants [Ogawa05, Yoshimura07] suggesting that this is a widely conserved pathway for preventing genomic and transcriptomic errors in the presence of ROS.

In humans, 8-oxo-dGMP is further degraded to 8-oxo-deoxyguanosine which can exit through the cell membrane, and end up in the urine where it is used as a diagnostic measurement of oxidative stress [Hayakawa95]. It is unclear what downstream steps are used to remove or recycle 8-oxo-GMP or 8-oxo-dGMP in other organisms.

Unification Links: PlantCyc:PWY-6502

Created 26-Apr-2010 by Dreher KA, TAIR


Haghdoost06: Haghdoost S, Sjolander L, Czene S, Harms-Ringdahl M (2006). "The nucleotide pool is a significant target for oxidative stress." Free Radic Biol Med 41(4);620-6. PMID: 16863995

Hayakawa95: Hayakawa H, Taketomi A, Sakumi K, Kuwano M, Sekiguchi M (1995). "Generation and elimination of 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate, a mutagenic substrate for DNA synthesis, in human cells." Biochemistry 34(1);89-95. PMID: 7819228

Klaus05: Klaus SM, Wegkamp A, Sybesma W, Hugenholtz J, Gregory JF, Hanson AD (2005). "A nudix enzyme removes pyrophosphate from dihydroneopterin triphosphate in the folate synthesis pathway of bacteria and plants." J Biol Chem 280(7);5274-80. PMID: 15611104

Maki92: Maki H, Sekiguchi M (1992). "MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis." Nature 355(6357);273-5. PMID: 1309939

Mo92: Mo JY, Maki H, Sekiguchi M (1992). "Hydrolytic elimination of a mutagenic nucleotide, 8-oxodGTP, by human 18-kilodalton protein: sanitization of nucleotide pool." Proc Natl Acad Sci U S A 89(22);11021-5. PMID: 1332067

Nunoshiba04: Nunoshiba T, Ishida R, Sasaki M, Iwai S, Nakabeppu Y, Yamamoto K (2004). "A novel Nudix hydrolase for oxidized purine nucleoside triphosphates encoded by ORFYLR151c (PCD1 gene) in Saccharomyces cerevisiae." Nucleic Acids Res 32(18);5339-48. PMID: 15475388

Ogawa05: Ogawa T, Ueda Y, Yoshimura K, Shigeoka S (2005). "Comprehensive analysis of cytosolic Nudix hydrolases in Arabidopsis thaliana." J Biol Chem 280(26);25277-83. PMID: 15878881

Rogacheva08: Rogacheva, M.V., Kuznetsova, S.A. (2008). "Repair of 8-oxoguanine in DNA. The mechanisms of enzymatic catalysis." Russian Chemical Reviews. 77(9): 765-788.

Taddei97: Taddei F, Hayakawa H, Bouton M, Cirinesi A, Matic I, Sekiguchi M, Radman M (1997). "Counteraction by MutT protein of transcriptional errors caused by oxidative damage." Science 278(5335);128-30. PMID: 9311918

Yoshimura07: Yoshimura K, Ogawa T, Ueda Y, Shigeoka S (2007). "AtNUDX1, an 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase, is responsible for eliminating oxidized nucleotides in Arabidopsis." Plant Cell Physiol 48(10);1438-49. PMID: 17804481

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

Dobrzanska02: Dobrzanska M, Szurmak B, Wyslouch-Cieszynska A, Kraszewska E (2002). "Cloning and characterization of the first member of the Nudix family from Arabidopsis thaliana." J Biol Chem 277(52);50482-6. PMID: 12399474

Frick94: Frick DN, Weber DJ, Gillespie JR, Bessman MJ, Mildvan AS (1994). "Dual divalent cation requirement of the MutT dGTPase. Kinetic and magnetic resonance studies of the metal and substrate complexes." J Biol Chem 1994;269(3);1794-803. PMID: 8294428

Fujikawa02: Fujikawa K, Yakushiji H, Nakabeppu Y, Suzuki T, Masuda M, Ohshima H, Kasai H (2002). "8-Chloro-dGTP, a hypochlorous acid-modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog." FEBS Lett 512(1-3);149-51. PMID: 11852070

Furuichi94: Furuichi M, Yoshida MC, Oda H, Tajiri T, Nakabeppu Y, Tsuzuki T, Sekiguchi M (1994). "Genomic structure and chromosome location of the human mutT homologue gene MTH1 encoding 8-oxo-dGTPase for prevention of A:T to C:G transversion." Genomics 24(3);485-90. PMID: 7713500

Ito05: Ito R, Hayakawa H, Sekiguchi M, Ishibashi T (2005). "Multiple enzyme activities of Escherichia coli MutT protein for sanitization of DNA and RNA precursor pools." Biochemistry 44(17);6670-4. PMID: 15850400

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Oda97: Oda H, Nakabeppu Y, Furuichi M, Sekiguchi M (1997). "Regulation of expression of the human MTH1 gene encoding 8-oxo-dGTPase. Alternative splicing of transcription products." J Biol Chem 272(28);17843-50. PMID: 9211940

Oda99: Oda H, Taketomi A, Maruyama R, Itoh R, Nishioka K, Yakushiji H, Suzuki T, Sekiguchi M, Nakabeppu Y (1999). "Multi-forms of human MTH1 polypeptides produced by alternative translation initiation and single nucleotide polymorphism." Nucleic Acids Res 27(22);4335-43. PMID: 10536140

Ponnambalam94: Ponnambalam S, Jackson AP, LeBeau MM, Pravtcheva D, Ruddle FH, Alibert C, Parham P (1994). "Chromosomal location and some structural features of human clathrin light-chain genes (CLTA and CLTB)." Genomics 24(3);440-4. PMID: 7713494

Sakai02a: Sakai Y, Furuichi M, Takahashi M, Mishima M, Iwai S, Shirakawa M, Nakabeppu Y (2002). "A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1." J Biol Chem 277(10);8579-87. PMID: 11756418

Sakumi93: Sakumi K, Furuichi M, Tsuzuki T, Kakuma T, Kawabata S, Maki H, Sekiguchi M (1993). "Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis." J Biol Chem 268(31);23524-30. PMID: 8226881

Tajiri95: Tajiri T, Maki H, Sekiguchi M (1995). "Functional cooperation of MutT, MutM and MutY proteins in preventing mutations caused by spontaneous oxidation of guanine nucleotide in Escherichia coli." Mutat Res 336(3);257-67. PMID: 7739614

Topp02: Topp H, Armbrust S, Lengger C, Schoch G, Davies J, Stichler W, Manz F, Fusch C (2002). "Renal excretion of 8-oxo-7,8-dihydro-2(')-deoxyguanosine: degradation rates of RNA and metabolic rate in humans." Arch Biochem Biophys 402(1);31-7. PMID: 12051680

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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