Identification and Characterization of Adenosine 5′-Tetraphosphate in Human Myocardial Tissue

Westhoff, Timm H.; Jankowski, Joachim; Schmidt, Sibylle; Luo, Jing; Giebing, G.; Schlüter, Hartmut; Tepel, Martín; Zidek, Walter; Giet, Markus van der

doi:10.1074/jbc.m300288200

Cited by 16 publications

(23 citation statements)

References 27 publications

(21 reference statements)

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“…Nucleoside 5′‐tetraphosphates are more abundant than nucleoside 5′‐pentaphosphates . Despite the similarity in structure, AP 4 has a longer biological half‐life in vivo than ATP …”

Section: Methodsmentioning

confidence: 99%

Several Polyphosphate Kinase 2 Enzymes Catalyse the Production of Adenosine 5′‐Polyphosphates

et al. 2019

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Polyphosphate kinases (PPKs) are involved in many metabolic processes; enzymes of the second family (PPK2) are responsible for nucleotide synthesis fuelled by the consumption of inorganic polyphosphate. They catalyse the phosphorylation of nucleotides with various numbers of phosphate residues, such as monophosphates or diphosphates. Hence, these enzymes are promising candidates for cofactor regeneration systems. Besides adenosine 5′‐triphosphate, PPK2s also catalyse the synthesis of highly phosphorylated nucleotides in vitro, as shown here for adenosine 5′‐tetraphosphate and adenosine 5′‐pentaphosphate. These unusually phosphorylated adenosine 5′‐polyphosphates add up to 50 % of the whole adenosine nucleotides in the assay. The two new products were chemically synthesised to serve as standards and compared with the two enzymatically produced compounds by high‐performance ion chromatography and 31P NMR analysis. This study shows that PPK2s are highly suitable for biocatalytic synthesis of different phosphorylated nucleotides.

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Section: Methodsmentioning

confidence: 99%

Several Polyphosphate Kinase 2 Enzymes Catalyse the Production of Adenosine 5′‐Polyphosphates

et al. 2019

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“…33 After preconstriction of renal vessels using Ang II and desensitization of P2X1/3 receptors using ␣,␤-meATP, there was a small vasodilation induced by high doses of AP4. It has been shown previously that AP4 can activate endothelial P2Y1 receptors in coronary arteries to induce vasodilation, 34 but in renal endothelium, P2Y1 receptors are not present. 30 Therefore, we speculate that the vasodilation is rather attributable to degradation of AP4 to ATP and its derivatives.…”

Section: Discussionmentioning

confidence: 99%

Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

Tölle

Jankowski

Schuchardt

et al. 2008

Circulation Research

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Abstract-Besides serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors still remains uncertain. The supernatant from mechanically stimulated human microvascular endothelial cells elicited a potent vasoconstrictive response in the isolated perfused rat kidney. Whereas a nonselective purinoceptor blocker blocked this vasoactivity most potently, the inhibition of the endothelin receptor by BQ123 weakly affected that vasoconstrictive response. As a compound responsible for that vasoconstrictive effect, we have isolated from HMECs and identified the mononucleotide adenosine 5Ј-tetraphosphate (AP4). This nucleotide proved to be the most potent vasoactive purinergic mediator identified to date, exerting the vasoconstriction predominantly through activation of the P2X1 receptor. The intraarterial application of AP4 in a Wistar-Kyoto rat induced a strong increase of the mean arterial pressure. The plasma concentration of AP4 is in the nanomolar range, which, in vivo, induces a significant change in the mean arterial pressure. To our knowledge, AP4, which exerts vasoactive effects, is the most potent endogenous mononucleotide identified to date in mammals. The effects of AP4, the plasma concentration of AP4, and its release suggest that this compound functions as an important vasoregulator.

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“…Very recently, Ap 4 has been identified in human myocardial tissue. The application of this nucleotide in isolated rat heart can produce vasodilatation (Westhoff et al, 2003).…”

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confidence: 99%

Adenosine Tetraphosphate, Ap₄, a Physiological Regulator of Intraocular Pressure in Normotensive Rabbit Eyes

Pintor

Peláez²,

Peral³

2003

J Pharmacol Exp Ther

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Adenosine 5Ј tetraphosphate, Ap 4 , is a natural nucleotide present in many biological systems. This nucleotide has been found as a constituent of the nucleotide pool present in the aqueous humor of New Zealand rabbits. HPLC analysis confirmed its identity and calculated its concentration levels to be 197 Ϯ 21 nM. When applied topically to the rabbit eyes, this mononucleotide produced a reduction in the intraocular pressure, which was dose-dependent. The pD 2 value calculated from the dose-response curve was 7.28 Ϯ 0.47, which is equivalent to 52.48 nM. The time course of such intraocular pressure reduction presented a maximal decrease of IOP to 75.1 Ϯ 2.3% compared with the vehicle control value (100%), and the effect lasted for more than 2 h. Cross-desensitization studies demonstrated that Ap 4 effect was mediated via a P2X receptor in this system. P2 receptor antagonists suramin, pyridoxal phosphate 6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS), and reactive blue 2 (RB-2) showed that only the latter was able to revert the effect of Ap 4 . Antagonists of adrenoceptors and cholinoceptors were able to partially reverse the effect of this nucleotide; this might indicate a connection with the neural mechanisms that control the intraocular pressure.

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Identification and Characterization of Adenosine 5′-Tetraphosphate in Human Myocardial Tissue

Cited by 16 publications

References 27 publications

Several Polyphosphate Kinase 2 Enzymes Catalyse the Production of Adenosine 5′‐Polyphosphates

Several Polyphosphate Kinase 2 Enzymes Catalyse the Production of Adenosine 5′‐Polyphosphates

Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

Adenosine Tetraphosphate, Ap₄, a Physiological Regulator of Intraocular Pressure in Normotensive Rabbit Eyes

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Identification and Characterization of Adenosine 5′-Tetraphosphate in Human Myocardial Tissue

Cited by 16 publications

References 27 publications

Several Polyphosphate Kinase 2 Enzymes Catalyse the Production of Adenosine 5′‐Polyphosphates

Several Polyphosphate Kinase 2 Enzymes Catalyse the Production of Adenosine 5′‐Polyphosphates

Adenosine 5′-Tetraphosphate Is a Highly Potent Purinergic Endothelium-Derived Vasoconstrictor

Adenosine Tetraphosphate, Ap4, a Physiological Regulator of Intraocular Pressure in Normotensive Rabbit Eyes

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Adenosine Tetraphosphate, Ap₄, a Physiological Regulator of Intraocular Pressure in Normotensive Rabbit Eyes