Disease relevance of Diadenosine tetraphosphate

• AppppA , ApppGpp , AppppG , ApppG , and ApppA rapidly accumulate to high levels in Salmonella typhimurium following exposure to a variety of oxidizing agents, but not to a variety of other stresses [1].
• We report here that several E. coli proteins bind AppppA, including the heat shock and oxidative stress proteins DnaK, GroEL, E89, C45 and C40 [2].
• The dinucleotide AppppA (5',5'''-P1, P4-diadenosine tetraphosphate) is rapidly synthesized in cells exposed to heat stress or oxidative stress [2].
• Inhibition of simian virus 40 DNA replication in vitro by poly(ADP-ribosyl)ated diadenosine tetraphosphate [3].
• The African swine fever virus (ASFV) g5R gene encodes a protein containing a Nudix hydrolase motif which in terms of sequence appears most closely related to the mammalian diadenosine tetraphosphate (Ap4A) hydrolases [4].

High impact information on Diadenosine tetraphosphate

• Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex [5].
• In addition, we show that apaH mutants, which have high basal levels of AppppA, are hypersensitive to killing by heat [2].
• Stress-induced AppppA accumulation has been observed in all cell types studied to date [2].
• Effect of diadenosine tetraphosphate microinjection on heat shock protein synthesis in Xenopus laevis oocytes [6].
• In this report, we used the radiolabeled purine analog, 99mTc diadenosine tetraphosphate (Ap4A; AppppA, P1,P4-di(adenosine-5')-tetraphosphate) and its analogue 99mTc AppCHClppA for imaging experimental atherosclerotic lesions in New Zealand White rabbits [7].

Chemical compound and disease context of Diadenosine tetraphosphate

• apaH- mutants lack the hydrolase responsible for degradation of AppppN dinucleotides in Escherichia coli and show a greater than or equal to 16-fold increase in AppppA under nonstress conditions [8].
• A total of 13 phosphonate analogues of bis(5'-adenosyl) tetraphosphate (AppppA) have been tested as substrates and inhibitors of the asymmetrically cleaving bis(5'-nucleosidyl) tetraphosphatase (NppppNase) from Artemia and the symmetrically cleaving NppppNase from Escherichia coli [9].
• Introduction of one methylene (as in I and III) [or bromomethylene (as in II)] group into AppppA results in a 3-15-fold increase of its affinity for lupin and Escherichia coli AppppA hydrolases [10].

Biological context of Diadenosine tetraphosphate

• High levels of AppppA have subsequently been shown to affect many cellular processes, including expression of catabolite repressible genes and the ability to survive starvation, oxidative stress and near-UV irradiation [2].
• We have previously demonstrated in a series of searches for antithrombotic agents that diadenosine 5',5"'-P1,P4-tetraphosphate (AppppA) and its analogues are competitive inhibitors of ADP-induced platelet aggregation [11].
• Cellular levels of diadenosine tetraphosphate (Ap4A) and adenosine tetraphospho-guanosine (Ap4G) were specifically measured during the cell cycle of Physarum polycephalum by a high-pressure liquid chromatographic method [12].
• Active site mutants of the Caenorhabditis elegans diadenosine tetraphosphate hydrolase had no activity, confirming that the same active site is responsible for nucleotide and PRPP hydrolysis [13].
• Asymmetric diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A) hydrolases play a major role in maintaining homeostasis by cleaving the metabolite diadenosine tetraphosphate (Ap(4)A) back into ATP and AMP [14].

Anatomical context of Diadenosine tetraphosphate

• Diadenosine tetraphosphatase, an enzyme splitting diadenosine tetraphosphate to AMP and ATP, has been purified to apparent homogeneity from a permanent cell line derived from a leukemic child [15].
• High diadenosine tetraphosphate (Ap4A) level in germ cells and embryos of sea urchin and Xenopus and its effect on DNA synthesis [16].
• The binding of adenosine(5')tetraphospho(5')adenosine to calf thymus histones measured by non-equilibrium dialysis [17].
• Identification and partial characterization of an adenosine(5')tetraphospho(5')adenosine hydrolase on intact bovine aortic endothelial cells [18].
• The diadenosine polyphosphates, diadenosine tetraphosphate and diadenosine pentaphosphate (Ap5A), can activate an ionotropic dinucleotide receptor that induces Ca2+ transients into synaptosomes prepared from rat brain [19].

Associations of Diadenosine tetraphosphate with other chemical compounds

• The Fhit tumor suppressor protein regulates the intracellular concentration of diadenosine triphosphate but not diadenosine tetraphosphate [20].
• The diadenosine polyphosphates diadenosine tetraphosphate (Ap4A) and diadenosine pentaphosphate (Ap5A) are costored with ATP and released in a calcium-dependent manner from neural preparations in vitro [21].
• Diadenosine pentaphosphate (AP5A) and diadenosine hexaphosphate (AP6A) are more potent than diadenosine tetraphosphate (AP4A) and diadenosine triphosphate (AP3A) and cause skeletal muscle vasoconstriction in rats [22].
• The biologically active dinucleotides adenosine(5')tetraphospho(5')adenosine (Ap4A) and adenosine(5')-triphospho(5')adenosine (Ap3A), which are both releasable into the circulation from storage pools in thrombocytes, are catabolized by intact bovine aortic endothelial cells [18].
• Secretion of adenosine(5')tetraphospho(5')adenosine (Ap4A) and ATP from perfused bovine adrenal glands stimulated with acetylcholine or elevated potassium levels was measured and compared with that of catecholamines [23].

Gene context of Diadenosine tetraphosphate

• The FHIT gene, located at the FRA3B fragile site of chromosome 3p14.2, encodes a 16.8 kD homologue of the yeast enzyme diadenosine tetraphosphate (Ap(4)A) hydrolase [24].
• An apaH mutation causes AppppA to accumulate and affects motility and catabolite repression in Escherichia coli [8].
• The contributions to substrate binding and catalysis of 13 amino acid residues of the Caenorhabditis elegans diadenosine tetraphosphate pyrophosphohydrolase (Ap(4)A hydrolase) predicted from the crystal structure of an enzyme-inhibitor complex have been investigated by site-directed mutagenesis [25].
• Ap4Aase and Ap3Aase were assayed in cytosolic rat brain extracts using fluorogenic analogues of the respective substrates diadenosine tetraphosphate (Ap4A) and diadenosine triphosphate (Ap3A) [26].
• HisRS also belongs to the group of aaRS that can rapidly synthesize diadenosine tetraphosphate, a compound that is suspected to be involved in several regulatory mechanisms of cell metabolism [27].

Analytical, diagnostic and therapeutic context of Diadenosine tetraphosphate

• Analysis of the catalytic and binding residues of the diadenosine tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans by site-directed mutagenesis [25].
• BACKGROUND: We have reported a similar cardioprotective effect and mechanism of diadenosine tetraphosphate (AP4A) and ischemic preconditioning in rat hearts [28].
• Crystallization of a complex of Caenorhabditis elegans diadenosine tetraphosphate hydrolase and a non-hydrolysable substrate analogue, AppCH2ppA [29].
• Clinical application of diadenosine tetraphosphate (Ap4A:F-1500) for controlled hypotension [30].
• Cardioprotective effect of diadenosine tetraphosphate (AP4A) cardioplegia in isolated rat hearts [31].

References