Storage, release, uptake, and inactivation of purines

Abstract

Adenine nucleotides are released into the interstitial space during platelet thrombus formation and neurotransmission. ATP has also been reported to be released from the heart and endothelial cells in some studies. Ecto ATPase, ADPase, and 5'-nucleotidase activities capable of hydrolyzing ATP sequentially t o adenosine are present in many cell types and may serve to terminate the actions of the nucleotides. The opposing effects of adenosine and ATP on the same cell types have suggested a modulatory role for adenosine on the actions of extracellular ATP and that the rates of hydrolysis of nucleotides might be regulated. Consistent with this it has been found that the balance between feedforward inhibition of 5'-nucleotidase by ADP andlor ATP and preferential delivery of AMP from ADPase to 5'-nucleotidase determines the rate of adenosine production and that this differs in different cell types. Alternatively, adenosine may be produced intracellularly as a result of an imbalance between energy demand and supply. There are at least two different cytosolic forms of 5'-nucleotidase. Degradation of ATP during increased metabolic activity results in an increase in intracellular AMP concentration. Either cytosolic enzyme has a high Km (2-5 mM) and would thus respond to this increase with a proportional rise in the rate of adenosine production. The nucleoside transporter i s essential to allow the diffusion of adenosine to extracellular receptor sites. In general, adenosine must be taken up via the nucleoside transporter before it is inactivated either by phosphorylation by adenosine kinase in the micromolar range or by deamination by adenosine deaminase at higher concentrations. o 1993 WiIey-Liss, Inc.

Mechanisms of apoptosis induced by purine nucleosides in astrocytes

“…Pretreatment of the cells with ␣,␤-Me-ADP, an inhibitor of ecto-5Ј-nucleotidase, increased significantly the amount of extracellular adenine-based nucleotides. Adenine nucleotides are the source of much of the extracellular adenosine in the central nervous system in physiological and pathological conditions (Meghji, 1993). In astrocyte cultures, extracellular adenosine is principally removed via metabolism to inosine by adenosine deaminase (Meghji et al, 1989;Ceballos et al, 1994).…”

5'-Nucleotidases, Nucleosides and their Distribution in the Brain: Pathological and Therapeutic Implications

“…Intracellularly and extracellularly, 5'NTs, which are integrant components of the endo-and ectonucleotidase enzyme cascade, catalyze the final step of nucleotide dephosphorylation (from NMPs to its corresponding nucleosides) [56][57][58][83][84][85][86]. This process contributes to the maintenance of nucleoside/nucleotide levels and the balance necessary to ensure their physiological functions in the brain and modulates the nucleoside effects on brain tissue cells via nucleoside levels, nucleoside transporters and their receptors [82,87].…”

“…The activity of cN-II may be enhanced by (deoxy)ATP, GTP and ADP [82,[139][140][141]. Cytosolic 5'-nucleotidase II has a phosphotransferase activity from 6-hydroxypurine monophosphates (phosphate donors) to phosphate acceptors, such as Guo, (deoxy)Ino and nucleoside analogs, to form monophosphate derivatives [85,133,[140][141][142][143], and plays a role in (i) purine nucleotide interconversion, (ii) the maintenance/modulation of intracellular 5-phosphoribosyl-1-pyrophosphate (PRPP) and purine nucleotide pools and (iii) the survival of cultured astrocytoma cells [81,133,144].…”

“…(1)) [56,[83][84][85][86]197]. The extracellular levels of Ado are formed extracellularly from ATP and released from cells that are regulated by e5'NT, ecto-adenosine kinase (ecto-ADK) and ecto-adenosine deaminase (ecto-ADA) [56,86,101,[198][199][200][201][202].…”

“…Thus, the increased extracellular nucleotide levels (e.g., ATP) in the synaptic cleft (e.g., under hypoxic/ischemic conditions) may cause an accumulation of NMPs (e.g., AMP) to a greater extent compared to nucleosides (e.g., Ado). The decrease in nucleoside triphosphate levels may result in relief of e5'NT inhibition and thereby elevate nucleoside levels and nucleoside transport into the brain cells anabolized into nucleoside mono-, di-and triphosphates derivatives [58,84,85,257]. During normoxic conditions (at 3.6 mM ATP levels) [133], extracellular nucleotides (e.g., ATP) are mainly catabolized into nucleosides (e.g., Ado) since the level of e5'NT inhibitor nucleoside triphosphates are lower than under ischemic conditions.…”