NUDT5 hydrolyzes oxidized deoxyribonucleoside diphosphates with broad substrate specificity

Kamiya, Hiroyuki; Hori, Mika; Arimori, Takao; Sekiguchi, Mutsuo; Yamagata, Yuriko; Harashima, Hideyoshi

doi:10.1016/j.dnarep.2009.07.011

Cited by 27 publications

(22 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also examined the proteins for a possible relationship between their primary structures and their ranges of substrate specificity. The three human proteins MTH1, MTH3, and NUDT5, as well as the S. cerevisiae protein Pcd1, can cleave various types of oxidized purine nucleotides, whereas the E. coli MutT and C. elegans NDX-1 proteins act strictly on 8-oxoGua-containing nucleotides (27,28,30), yet specific sequence motifs for distinguishing these two groups of proteins have not been identified. The substrate recognition and binding may be achieved by a few amino acid residues located near or within the active center, and thus, elucidation of the three-dimensional structures is essential for solving this problem.…”

Section: Discussionmentioning

confidence: 99%

“…Actions of MTH3 on Other Types of Oxidized Nucleotides-It has been shown that the human MTH1 and NUDT5 proteins possess the ability to hydrolyze other types of oxidized nucleotides besides those containing 8-oxo-Gua (27,28). To determine whether MTH3 has such an activity, three types of oxidized nucleoside diphosphates were treated with MTH3, and the reaction products were analyzed by HPLC.…”

Section: Purification Of Enzymes Acting On Oxidized Guanine-containinmentioning

confidence: 99%

See 1 more Smart Citation

Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates

Takagi

Setoyama

Ito

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: An oxidized guanine, 8-oxo-7,8-dihydroguanine, induces base mispairing, thereby altering genetic information. Results: Human MTH3 degrades 8-oxoguanine-containing nucleoside diphosphates to prevent misincorporation of 8-oxoguanine into DNA and RNA. Conclusion: MTH3 is closely related to MTH1 and MTH2 but differs in substrate specificity. Significance: MTH3 may be involved in maintaining the high fidelity of DNA replication as well as transcription under oxidative stress.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Purification Of Enzymes Acting On Oxidized Guanine-containinmentioning

confidence: 99%

Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates

Takagi

Setoyama

Ito

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The broad substrate specificity of MTH1 suggests its versatile roles in multiple sanitization pathways. Furthermore, human NUDT5 specifically degrades 8-oxo-dGDP (Sekiguchi and Tsuzuki, 2002;Ishibashi et al, 2003;Kamiya et al, 2009). All of these proteins significantly suppress the mutator phenotype in mutT-deficient E. coli mutant cells (Ishibashi et al, 2003;Kamiya et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, human NUDT5 specifically degrades 8-oxo-dGDP (Sekiguchi and Tsuzuki, 2002;Ishibashi et al, 2003;Kamiya et al, 2009). All of these proteins significantly suppress the mutator phenotype in mutT-deficient E. coli mutant cells (Ishibashi et al, 2003;Kamiya et al, 2009). Thus, it is quite possible that other oxidized nucleotides with potent mutagenicity are continually generated by ROS in E. coli and eukaryotes, including C. intestinalis.…”

Section: Discussionmentioning

confidence: 99%

“…E. coli Orf135 also has a pyrophosphohydrolase activity that hydrolyzes 2-oxodATP to 2-oxo-dAMP (Kamiya et al, 2003). In addition, MutT and human NUDT5 have 8-oxo-dGDPase activity that degrades 8-oxo-dGDP to 8-oxo-dGMP (Sekiguchi and Tsuzuki, 2002;Ishibashi et al, 2003;Kamiya et al, 2009). 8-oxo-dGMP and 2-oxo-dAMP are not rephosphorylated to the triphosphate form and therefore are not incorporated into DNA by DNA polymerases.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CiMutT, an asidian MutT homologue, has a 7, 8-dihydro-8-oxo-dGTP pyrophosphohydrolase activity responsible for sanitization of oxidized nucleotides in Ciona intestinalis

2010

View full text Add to dashboard Cite

The oxidized nucleotide precursors 7, 8-dihydro-8-oxo-dGTP (8-oxo-dGTP) and 1, 2-dihydro-2-oxo-dATP (2-oxo-dATP) are readily incorporated into nascent DNA strands during replication, which would cause base substitution mutations. E. coli MutT and human homologue hMTH1 hydrolyze 8-oxo-dGTP, thereby preventing mutations. In this study, we searched for hMTH1 homologues in the ascidian Ciona intestinalis using the NCBI-BLAST database. Among several candidates, we focused on one open reading frame, designated as CiMutT, because of its high degree of identity (41.7%) and similarity (58.3%) to the overall amino acid sequence of hMTH1, including the Nudix box. CiMutT significantly suppressed the mutator activity of E. coli mutT mutant. Purified CiMutT had a pyrophosphohydrolase activity that hydrolyzed 8-oxo-dGTP to 8-oxo-dGMP and inorganic pyrophosphate. It had a pH optimum of 9.5 and Mg ++ requirement with optimal activity at 5 mM. The activity of CiMutT for 8-oxo-dGTP was comparable to that of hMTH1, while it was 100-fold lower for 2-oxo-dATP than that of hMTH1. These facts indicate that CiMutT is a functional homologue of E. coli MutT. In addition, the enzyme hydrolyzed all four of the unoxidized nucleoside triphosphates, with a preference for dATP. The specific activity for 8-oxo-dGTP was greater than that for unoxidized dATP and dGTP. These results suggest that CiMutT has the potential to prevent mutations by 8-oxo-dGTP in C. intestinalis.

show abstract

Substrate ambiguity among the nudix hydrolases: biologically significant, evolutionary remnant, or both?

McLennan

2012

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Many members of the nudix hydrolase family exhibit considerable substrate multispecificity and ambiguity, which raises significant issues when assessing their functions in vivo and gives rise to errors in database annotation. Several display low antimutator activity when expressed in bacterial tester strains as well as some degree of activity in vitro towards mutagenic, oxidized nucleotides such as 8-oxo-dGTP. However, many of these show greater activity towards other nucleotides such as ADP-ribose or diadenosine tetraphosphate (Ap(4)A). The antimutator activities have tended to gain prominence in the literature, whereas they may in fact represent the residual activity of an ancestral antimutator enzyme that has become secondary to the more recently evolved major activity after gene duplication. Whether any meaningful antimutagenic function has also been retained in vivo requires very careful assessment. Then again, other examples of substrate ambiguity may indicate as yet unexplored regulatory systems. For example, bacterial Ap(4)A hydrolases also efficiently remove pyrophosphate from the 5' termini of mRNAs, suggesting a potential role for Ap(4)A in the control of bacterial mRNA turnover, while the ability of some eukaryotic mRNA decapping enzymes to degrade IDP and dIDP or diphosphoinositol polyphosphates (DIPs) may also be indicative of new regulatory networks in RNA metabolism. DIP phosphohydrolases also degrade diadenosine polyphosphates and inorganic polyphosphates, suggesting further avenues for investigation. This article uses these and other examples to highlight the need for a greater awareness of the possible significance of substrate ambiguity among the nudix hydrolases as well as the need to exert caution when interpreting incomplete analyses.

show abstract

NUDT5 hydrolyzes oxidized deoxyribonucleoside diphosphates with broad substrate specificity

Cited by 27 publications

References 40 publications

Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates

Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates

CiMutT, an asidian MutT homologue, has a 7, 8-dihydro-8-oxo-dGTP pyrophosphohydrolase activity responsible for sanitization of oxidized nucleotides in Ciona intestinalis

Substrate ambiguity among the nudix hydrolases: biologically significant, evolutionary remnant, or both?

Contact Info

Product

Resources

About