Nucleoside recycling in the brain and the nucleosidome: a complex metabolic and molecular cross-talk between the extracellular nucleotide cascade system and the intracellular nucleoside salvage

Abstract

The transports of nucleosides from blood into\ud neurons and astrocytes are essential prerequisites to enter\ud their metabolic utilization in brain. Adult brain does not\ud possess the de novo nucleotide synthesis, and maintains its\ud nucleotide pools by salvaging preformed nucleosides\ud imported from liver. Once nucleosides enter the brain\ud through the blood brain barrier and the nucleoside transporters,\ud they become obligatory precursors for the synthesis\ud of RNA and DNA and a plethora of other important\ud functions. However, an aliquot of nucleotides are transferred\ud into vesicular nucleotide transporters, and then in the\ud extracellular space by exocytosis of the vesicles, where\ud ATP and UTP interact with a vast heterogeneity of purine\ud and pyrimidine receptors. Their signal actions are terminated\ud by the ectonucleotidase cascade system, which\ud degrades ATP and UTP into adenosine and uridine,\ud respectively. The low specificity of the vesicular nucleotide\ud transporters may explain the presence in the extracellular\ud space of GTP and CTP, which are equally degraded to their\ud respective nucleosides by the ectonucleotidases. The main\ud four nucleosides are re-imported either into the same cell,\ud or in adjacent cells, e.g. between two astrocytes, or\ud between a neuron and an astrocyte, to regenerate nucleoside\ud triphosphates. The molecular network of this metabolic\ud cross-talk, involving the ectonucleotidases, the\ud nucleoside transporters, the nucleotide salvage system, the\ud nucleotide transport into the vesicular nucleotide transporters,\ud and the exocytotic release of nucleotides, called by\ud us the ‘‘nucleosidome’’, serves the nucleoside recycling in\ud the brain, with a considerable spatial–temporal advantage

The Inside Story of Adenosine

“…In this respect, the discrepancies among results obtained in studies using different experimental approaches are not at all surprising. Ado is usually kept at a very low concentration in the body—below 1 µM [ 2 , 3 ]. In a healthy organism, its concentration can increase only as a consequence of ATP breakdown, which can occur both inside or outside the cell.…”

“…As for many other compounds, liver synthesizes nucleotides for exportation, and, since de novo synthesis produces phosphorylated compounds, they must be dephosphorylated into nucleosides and in part phosphorolytically cleaved into bases and ribose-1-phosphate (Rib-1-P), in order to leave the hepatocyte, enter the blood flux, and be taken up by cells and organs in the body. Therefore, adenosine (Ado) is synthesized mainly in the liver as the product of dephosphorylation of AMP, and travels in the blood at a concentration of about 0.5 µM [ 2 , 3 ]. Eventually, Ado enters cells mainly through equilibrative nucleoside transporters (ENT) and is phosphorylated by Ado kinase (AdoK) and adenylate kinases into ADP.…”

“…Eventually, Ado enters cells mainly through equilibrative nucleoside transporters (ENT) and is phosphorylated by Ado kinase (AdoK) and adenylate kinases into ADP. The newly synthesized ADP and ADP, arising from the kinase reactions in which ATP is used as a phosphate donor, then enter mitochondria for oxidative phosphorylation [ 3 ]. Therefore, the uptake of Ado requires an active oxidative metabolism to be driven.…”

Purines: From Diagnostic Biomarkers to Therapeutic Agents in Brain Injury

“…The half-life of adenosine in blood is of the order of 20-60 s [56][57][58] . Inside red blood cells adenosine can be converted to AMP or inosine and hypoxanthine, the latter of which can enter the purine salvage pathway, the primary means by which erythrocytes, the heart and indeed the brain reconstitute adenine nucleotides (Figure 2) [36,[59][60][61] . This complexity of dynamic processing makes the purines hard to measure in clinical samples, and has been a barrier to their adoption as biomarkers to provide clinical information.…”

“…While the loss of purines into the blood stream serves as a biomarker of metabolic crisis and may be useful in the diagnosis of an acute cerebral emergency, their loss deprives the brain of the substrates necessary to synthesise ATP. This is because the brain, like the metabolically highly active heart, utilises the purine salvage pathway (PSP; Figure 2) as the primary means by which to synthesise adenine nucleotides, in contrast to the slower, and metabolically more expensive de novo synthesis route [36,[59][60][61] . The PSP, which is present in both neurones and glia, comprises two branches, one catalysed by adenine phosphoribosyltransferase (APRT), and the other by hypoxanthine phosphoribosyltransferase (HPRT), the enzyme deficient in Lesch-Nyhan syndrome [69] .…”