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Literature summary for 2.7.99.B1 extracted from

  • Marriott, A.; Copeland, N.; Cunningham, R.; Wilkinson, M.; McLennan, A.; Jones, N.
    Diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication (2015), DNA Repair, 33, 90-100.
    View publication on PubMed
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Inhibitors

Inhibitors Comment Organism Structure
2-[(3,5-dibromo-4-methylphenyl)amino]-N'-[(E)-(2-hydroxy-5-nitrophenyl)methylidene]acetohydrazide the Lig III inhibitor L67 leads to a 5fold increase in Ap4A, suggesting that Lig III may synthesize Ap4A in vivo when prevented from associating with DNA even in the absence of DNA damage Cricetulus griseus
DNA the enzyme activity is inhibited by DNA-binding Cricetulus griseus
additional information the Lig I-specific inhibitor L82, which prevents DNA-binding but not adenylation activity, causes only a slight, 1.3fold increase in the level of Ap4A in AA8 cells treated for 18 h Cricetulus griseus

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2 ATP Cricetulus griseus the enzyme synthesizes Ap4A by transfer of AMP from the enzyme-adenylate intermediate to an ATP acceptor diadenosine 5',5'''-P1,P4-tetraphosphate + diphosphate
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Organism

Organism UniProt Comment Textmining
Cricetulus griseus
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Source Tissue

Source Tissue Comment Organism Textmining
CHO-AA8 cell
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 Cricetulus griseus
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EM-9 cell
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 Cricetulus griseus
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Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2 ATP the enzyme synthesizes Ap4A by transfer of AMP from the enzyme-adenylate intermediate to an ATP acceptor Cricetulus griseus diadenosine 5',5'''-P1,P4-tetraphosphate + diphosphate
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 ?

Synonyms

Synonyms Comment Organism
LigIII
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 Cricetulus griseus

Expression

Organism Comment Expression
Cricetulus griseus stress-induced increases inAp4A by DNA addition. Lig III-mediated Ap4A synthesis in response to an increased level of unrepaired strand breaks in APTX-deficient cells up

General Information

General Information Comment Organism
malfunction deletion of Lig I (PFL13) causes only a slight, 1.6fold increase in background Ap4A but has no effect on the level reached after treatment with MMC, indicating that Lig I cannot be responsible for the MMC-induced increase in Ap4A. Lig III, cf. EC 6.5.1.1, is the most likely, if not sole ligase, contributing to MMC-enhanced Ap4A synthesis. Normal NUDT2 expression does appear to limit the extent of Ap4A accumulation after DNA damage, but suppression of the activity of a hydrolytic activity such as the NUDT2 Ap4A hydrolase does not seem to be reponsible for Ap4A increase after DNA damage Cricetulus griseus
metabolism no significant difference in the activity of NUDT2 between AA8 cells when cell extracts are assayed for NUDT2 activity in the 16-20 kDa region or when AA8 cells are treated with MMC Cricetulus griseus
physiological function non-cytotoxic doses of certain DNA damaging agents increase diadenosine 5',5'''-P1,P4-tetraphosphate, Ap4A, to concentrations that can inhibit the initiation of DNA replication in a mammalian cell-free system and provide some pointers to the mechanism underlying this increase and its function. Accumulation occurs in vivo of ADP-ribosylated derivatives of Ap4A in response to DNA damage. Lig III is the most likely, if not sole ligase, contributing to MMC-enhanced Ap4A synthesis. Lig III-mediated Ap4A synthesis in response to an increased level of unrepaired strand breaks in APTX-deficient cells Cricetulus griseus