NUDT5, (10p14) YSA1 ADP-sugar pyrophosphatase

https://www.ncbi.nlm.nih.gov/gene/11164

Also known as

YSA1; YSA1H; YSAH1; hNUDT5

Summary

This gene belongs to the Nudix (nucleoside diphosphate linked moiety X) hydrolase superfamily. The encoded enzyme catalyzes the hydrolysis of modified nucleoside diphosphates, including ADP-ribose (ADPR) and 8-oxoGua-containing 8-oxo-dADP and 8-oxo-dGDP. Protein-bound ADP ribose can be hazardous to the cell because it can modify some amino acid residues, resulting in the inhibition of ATP-activated potassium channels. 8-oxoGua is an oxidized form of guanine that can potentially alter genetic information by pairing with adenine and cytosine in RNA. Presence of 8-oxoGua in RNA results in formation of abnormal proteins due to translational errors. [provided by RefSeq, Aug 2013]

Expression

Ubiquitous expression in liver (RPKM 12.0), skin (RPKM 11.4) and 25 other tissues See more

Orthologs

mouse all

Preferred Names

ADP-sugar pyrophosphatase

Names

8-oxo-dGDP phosphatase

nuclear ATP-synthesis protein NUDIX5

nudix (nucleoside diphosphate linked moiety X)-type motif 5

NP_001308576.1

• EC 2.7.7.96

• EC 3.6.1.13

• EC 3.6.1.58

Related articles in PubMed

1. Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells. Page BDG, et al. Nat Commun, 2018 Jan 17. PMID 29343827, Free PMC Article
2. Lowered Nudix type 5 expression leads to cellular senescence in IMR-90 fibroblast cells. Zhang L, et al. Free Radic Res, 2013 Jul. PMID 23581889
3. [Mechanistic insight into hydrolysis of oxidized nucleotide diphosphates by human NUDT5]. Arimori T, et al. Fukuoka Igaku Zasshi, 2011 Nov. PMID 22351996
4. Lowered nudix type 5 (NUDT5) expression leads to cell cycle retardation in HeLa cells. Zhang LQ, et al. Mol Cell Biochem, 2012 Apr. PMID 22200976
5. Diverse substrate recognition and hydrolysis mechanisms of human NUDT5. Arimori T, et al. Nucleic Acids Res, 2011 Nov 1. PMID 21768126, Free PMC Article

GeneRIFs: Gene References Into Functions

1. Data suggest that targeting nudix hydrolase 5 (NUDT5) may represent a promising new therapeutic approach for breast cancer treatment.
2. In the presence of pyrophosphate, ADP-ribose is used by the pyrophosphatase NUDIX5 to generate nuclear ATP.
3. The NUDT5 protein could play significant roles in the prevention of RNA oxidation and survival in human fibroblast cells.
4. Results suggest that the NUDT5 protein may play significant roles in regulating the G1-S transition in HeLa cells.
5. The human NUDT5, which has an intrinsic activity to cleave ADP sugars to AMP and sugar phosphate, possesses the ability to degrade 8-oxo-dGDP to the monophosphate.
6. The broad substrate specificity of hNUDT5 is achieved by a diversity of not only substrate recognition, but also hydrolysis mechanisms.
7. human MTH1, MTH2, and NUDT5 proteins act as a defense against the mutagenesis induced by oxidized dGTP.
8. NUDT5 protein eliminates various oxidized deoxyribonucleoside diphosphates from the nucleotide pool and prevents their toxic effects.
9. Results report the crystal structure of hNUDT5 in complex with a non-hydrolyzable ADPR analogue, alpha,beta-methyleneadenosine diphosphoribose, and three Mg(2+) ions representing the transition state of the enzyme during catalysis.
10. degrades 8-oxo-dGDP to 8-oxo-dGMP, an unusable form for DNA synthesis, and promotes the cleavage of 8-oxo-dGTP by MTH1 to yield 8-oxo-dGMP also

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NUDT3 (6p21.31), DIPP1, difosfoinositolipolyfosfaattihydrolaasi 1

https://www.ncbi.nlm.nih.gov/gene/11165

Also known as

DIPP; DIPP1; DIPP-1

Summary

NUDT3 belongs to the MutT, or Nudix, protein family. Nudix proteins act as homeostatic checkpoints at important stages in nucleoside phosphate metabolic pathways, guarding against elevated levels of potentially dangerous intermediates, like 8-oxo-dGTP, which promotes AT-to-CG transversions (Safrany et al., 1998 [PubMed 9822604]).[supplied by OMIM, Feb 2011]

Expression

Ubiquitous expression in brain (RPKM 33.6), thyroid (RPKM 19.6) and 25 other tissues See more

Orthologs mouse all

 

 Structure, history

NP_006694.1  diphosphoinositol polyphosphate phosphohydrolase 1

 

 2002:

 Nudix hydrolases that degrade dinucleoside and diphosphoinositol
            polyphosphates also have 5-phosphoribosyl 1-pyrophosphate (PRPP)
            pyrophosphatase activity that generates the glycolytic activator
            ribose 1,5-bisphosphate

 1999:

  Site-directed mutagenesis of diphosphoinositol polyphosphate
            phosphohydrolase, a dual specificity NUDT enzyme that attacks
            diadenosine polyphosphates and diphosphoinositol polyphosphates

1998: 

A novel context for the 'MutT' module, a guardian of cell
            integrity, in a DIPP, diphosphoinositol polyphosphate phosphohydrolase

 NUDIX BOX 51-72  ggmepeeeps vaavrevcee ag

ORIGIN      
        1 mmklksnqtr tydgdgykkr aaclcfrses eeevllvsss rhpdrwivpg ggmepeeeps
       61 vaavrevcee agvkgtlgrl vgifenqerk hrtyvyvliv tevledweds vnigrkrewf
      121 kiedaikvlq yhkpvqasyf etlrqgysan ngtpvvatty svsaqssmsg ir
//

Preferred Names

diphosphoinositol polyphosphate phosphohydrolase 1

Names

diadenosine 5',5'''-P1,P6-hexaphosphate hydrolase 1

nucleoside diphosphate-linked moiety X motif 3

nudix (nucleoside diphosphate linked moiety X)-type motif 3

nudix motif 3

NP_006694.1

• EC 3.6.1.52

Related articles in PubMed

1. Nudt3 is an mRNA decapping enzyme that modulates cell migration. Grudzien-Nogalska E, et al. RNA, 2016 May. PMID 26932476, Free PMC Article
2. NUDT3 rs206936 is associated with body mass index in obese Japanese women. Kitamoto A, et al. Endocr J, 2013. PMID 23708086
3. Crystal structure of human diphosphoinositol phosphatase 1. Thorsell AG, et al. Proteins, 2009 Oct. PMID 19585659
4. Site-directed mutagenesis of diphosphoinositol polyphosphate phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine polyphosphates and diphosphoinositol polyphosphates. Yang X, et al. J Biol Chem, 1999 Dec 10. PMID 10585413
5. The diadenosine hexaphosphate hydrolases from Schizosaccharomyces pombe and Saccharomyces cerevisiae are homologues of the human diphosphoinositol polyphosphate phosphohydrolase. Overlapping substrate specificities in a MutT-type protein. Safrany ST, et al. J Biol Chem, 1999 Jul 30. PMID 10419486

See all (24) citations in PubMed

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GeneRIFs: Gene References Into Functions

1. Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals
2. results suggest that NUDT3 rs206936 is associated with body mass index in Japanese women

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NUDT2 (9p13.3) , APAH1 (diadenosine tetraphosphatase)

https://www.ncbi.nlm.nih.gov/gene/318

APAH1

Summary

This gene encodes a member of the MutT family of nucleotide pyrophosphatases, a subset of the larger NUDIX hydrolase family. The gene product possesses a modification of the MutT sequence motif found in certain nucleotide pyrophosphatases. The enzyme asymmetrically hydrolyzes Ap4A to yield AMP and ATP and is responsible for maintaining the intracellular level of the dinucleotide Ap4A, the function of which has yet to be established. This gene may be a candidate tumor suppressor gene. Alternative splicing has been observed at this locus and four transcript variants, all encoding the same protein, have been identified. [provided by RefSeq, Sep 2011]

Expression

Ubiquitous expression in ovary (RPKM 11.6), prostate (RPKM 10.9) and 25 other tissues See more

Orthologs

mouse all

Preferred Names

bis(5'-nucleosyl)-tetraphosphatase [asymmetrical]

Names

Ap4A hydrolase 1

Ap4Aase

bis(5'-nucleosyl)-tetraphosphatase (asymmetrical)

diadenosine 5',5'''-P1,P4-tetraphosphate asymmetrical hydrolase

diadenosine 5',5''-P1,P4-tetraphosphate pyrophosphohydrolase

diadenosine tetraphosphatase

nucleoside diphosphate-linked moiety X motif 2

nudix (nucleoside diphosphate linked moiety X)-type motif 2

nudix motif 2

NP_001152.1

• EC 3.6.1.17

 Structure, history 

  NP_001152.1  bis(5'-nucleosyl)-tetraphosphatase [asymmetrical] 

1991, Dinucleoside tetraphosphatase from human blood cells. Purification
            and characterization as a high specific activity enzyme recognized
            by an anti-rat tetraphosphatase antibody

Conserved Domains (1) summary

cd03428
Location:2 → 140

Ap4A_hydrolase_human_like; Diadenosine tetraphosphate (Ap4A) hydrolase is a member of the Nudix hydrolase superfamily. Ap4A hydrolases are well represented in a variety of prokaryotic and eukaryotic organisms. Phylogenetic analysis reveals two distinct subgroups where plant ...

Related articles in PubMed

1. NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes. Marriott AS, et al. PLoS One, 2016. PMID 27144453, Free PMC Article
2. Crystal structure of wild-type and mutant human Ap4A hydrolase. Ge H, et al. Biochem Biophys Res Commun, 2013 Mar 1. PMID 23384440
3. Nudix-type motif 2 in human breast carcinoma: a potent prognostic factor associated with cell proliferation. Oka K, et al. Int J Cancer, 2011 Apr 15. PMID 20533549
4. 1H, 13C, and 15N resonance assignments of the 17 kDa Ap4A hydrolase from Homo sapiens in the presence and absence of ATP. Swarbrick JD, et al. J Biomol NMR, 2005 Feb. PMID 15772762
5. Structure and substrate-binding mechanism of human Ap4A hydrolase. Swarbrick JD, et al. J Biol Chem, 2005 Mar 4. PMID 15596429

See all (25) citations in PubMed

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GeneRIFs: Gene References Into Functions

1. NUDT2 is a novel complex formation enhancing factor regulating mTORC1-Rag GTPase signaling that is crucial for cell growth control.
2. Regulation of gene expression is one of several roles proposed for the stress-induced nucleotide diadenosine tetraphosphate (Ap4A). We have examined this directly by a comparative RNA-Seq analysis of KBM-7 chronic myelogenous leukemia cells and KBM-7 cells in which the NUDT2 Ap4A hydrolase gene had been disrupted (NuKO cells), causing a 175-fold increase in intracellular Ap4A.
3. This paper presents the crystal structure of wild-type and E58A mutant human Ap4A hydrolase.
4. High NUDT2 is associated with breast carcinoma.
5. Observational study of gene-disease association. (HuGE Navigator)
6. In this study the authors present data demonstrating that the SARS-CoV 7a protein interacts with human Ap4A-hydrolase (asymmetrical diadenosine tetraphosphate hydrolase, EC 3.6.1.17).
7. NMR resonance assignments
8. crystallographic structure and substrate-binding mechanism of Ap4A hydrolase

 

NUDT1 (7p22.3) MTH1 (8-oxodGTPase) (2-OH-dATPdiphosphatase)

NUDIX1
https://www.ncbi.nlm.nih.gov/gene/4521

Also known as

MTH1

Summary

Misincorporation of oxidized nucleoside triphosphates into DNA/RNA during replication and transcription can cause mutations that may result in carcinogenesis or neurodegeneration. The protein encoded by this gene is an enzyme that hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP, to monophosphates, thereby preventing misincorporation. The encoded protein is localized mainly in the cytoplasm, with some in the mitochondria, suggesting that it is involved in the sanitization of nucleotide pools both for nuclear and mitochondrial genomes. Several alternatively spliced transcript variants, some of which encode distinct isoforms, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A single-nucleotide polymorphism that results in the production of an additional, longer isoform (p26) has been described. [provided by RefSeq, Jul 2008]

Expression

Broad expression in bone marrow (RPKM 17.0), testis (RPKM 13.9) and 24 other tissues See more

Preferred Names

7,8-dihydro-8-oxoguanine triphosphatase

Names

2-hydroxy-dATP diphosphatase

8-oxo-7,8-dihydrodeoxyguanosine triphosphatase

8-oxo-7,8-dihydroguanosine triphosphatase

8-oxo-dGTPase

mutT human homolog 1

nucleoside diphosphate-linked moiety X motif 1

nucleoside diphosphate-linked moiety X-type motif 1

nudix (nucleoside diphosphate linked moiety X)-type motif 1

nudix motif 1

NP_002443.3

• EC 3.6.1.55

• EC 3.6.1.56

Structure, History  , many isoforms.
Ex. isoform p18,  https://www.ncbi.nlm.nih.gov/protein/NP_945188.1
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. 

Conserved Domains (1) summary

cd03427
Location:6 → 140

MTH1; MutT homolog-1 (MTH1) is a member of the Nudix hydrolase superfamily. MTH1, the mammalian counterpart of MutT, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP and 2-hydroxy-ATP, to monophosphates, thereby preventing the ...

Related articles in PubMed

1. hMTH1 is required for maintaining migration and invasion potential of human thyroid cancer cells. Arczewska KD, et al. DNA Repair (Amst), 2018 Sep. PMID 30055508
2. MTH1 deficiency selectively increases non-cytotoxic oxidative DNA damage in lung cancer cells: more bad news than good? Abbas HHK, et al. BMC Cancer, 2018 Apr 16. PMID 29661172, Free PMC Article
3. (S)-crizotinib induces apoptosis in human non-small cell lung cancer cells by activating ROS independent of MTH1. Dai X, et al. J Exp Clin Cancer Res, 2017 Sep 7. PMID 28882182, Free PMC Article
4. Association of MTH1 expression with the tumor malignant potential and poor prognosis in patients with resected lung cancer. Fujishita T, et al. Lung Cancer, 2017 Jul. PMID 28577950
5. Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity. Waz S, et al. J Biol Chem, 2017 Feb 17. PMID 28035004, Free PMC Article

See all (98) citations in PubMed

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GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. overall our cell viability data indicates that targeting MTH1 will likely not be an across-the-board effective non-small cell lung cancer therapeutic strategy; rather it induces non-cytotoxic DNA damage that could promote cancer heterogeneity and evolution.
2. MTH1 is required for maintaining migration and invasion potential of human thyroid cancer cells.
3. PRDX1 and MTH1 cooperate to prevent accumulation of oxidized guanine in the genome
4. Results provide evidence that MTH1 is not essential for cancer cell survival.
5. CDT1, MCM7, and NUDT1 were shown to be up-regulated in hepatocellular carcinoma tissues and provide a more accurate diagnosis than alpha-fetal protein alone.
6. Our results reveal a novel antitumor mechanism of (S)-crizotinib in NSCLC which involves activation of ROS-dependent ER stress apoptotic pathway and is independent of MTH1 inhibition
7. this study showed that MTH1 protein expression was closely related to factors associated with a high malignant potential and poor patient survival
8. method for predicting individual residue contributions to enzyme specificity and binding-site energies, and its application to MTH1.
9. Data indicate the specificity of the enzyme 8-oxo-dGTPase MTH1 toward the substrate 8-oxo-dGTP.
10. We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.

 

Nudix hydrolases are found in all classes of organism and hydrolyse a wide range of organic pyrophosphates, including nucleoside di- and triphosphates, dinucleoside and diphosphoinositol polyphosphates, nucleotide sugars and RNA caps, with varying degrees of substrate specificity. Some superfamily members, such as Escherichia coli MutT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In prokaryotes and simple eukaryotes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Mammals have around 24 Nudix genes, several of which encode more than one variant. This review integrates the sizeable recent literature on these proteins with information from global functional genomic studies to provide some insights into the possible roles of different superfamily members in cellular metabolism and homeostasis and to stimulate discussion and further research into this ubiquitous protein family.

Fosfaattiyhdisteiden siivous solussa "Hausekeeping". NUDIX- superperhe

https://www.ncbi.nlm.nih.gov/pubmed/16378245

PI(4,5)P2 ja adaptiivinen immuunipuolustus

https://www.researchgate.net/publication/318500934_Cortical_actin_recovery_at_the_immunological_synapse_
leads_to_termination_of_lytic_granule_secretion_in_cytotoxic_T_lymphocytes

http://www.pnas.org/content/114/32/E6585

Significance

Cytotoxic T lymphocytes (CTLs) destroy virally infected and tumor cells through the directed secretion of specialized lysosomes called “lytic granules.” Because a single CTL must direct its cytotoxic activities only against specific targets but can sequentially kill multiple cells, granule secretion must be tightly controlled. We demonstrate here that dynamic regulation of the cortical actin cytoskeleton is critical for both the initiation and termination of secretion. We further link actin dynamics with phosphatidylinositol 4,5-bisphosphate (PIP₂) levels and provide evidence that lytic granule delivery initiates cortical actin recovery and the cessation of secretion. Our results suggest that actin both regulates and is regulated by secretion, providing a mechanism by which CTLs control their ability to kill targets serially during immune responses.