Metabolic Network of Nucleosides in the Brain

Abstract

Brain relies on circulating nucleosides, mainly synthesised de novo in the liver, for the synthesis of nucleotides, RNA, nuclear and mitochondrial DNA, coenzymes, and pyrimidine sugar- and lipid-conjugates. Essentially, the paths of nucleoside salvage in the brain include a two step conversion of inosine and guanosine to IMP and GMP, respectively, and a one step conversion of adenosine, uridine, and cytidine, to AMP, UMP, and CMP, respectively. With the exception of IMP, the other four nucleoside monophosphates are converted to their respective triphosphates via two successive phosphorylation steps. Brain ribonucleotide reductase converts nucleoside diphosphates to their deoxy counterparts. The delicate qualitative and quantitative balance of intracellular brain nucleoside triphosphates is maintained by the relative concentrations of circulating nucleosides, the specificity and the K(m) values of the transport systems and of cytosolic and mitochondrial nucleoside kinases and 5'-nucleotidases, and the relative rates of nucleoside triphosphate extracellular release. A cross talk between extra- and intra-cellular nucleoside metabolism exists, in which released nucleoside triphosphates, utilised as neuroactive signals, are catabolised by a membrane bound ectonucleotidase cascade system to their respective nucleosides, which are uptaken into brain cytosol, and converted back to nucleoside triphosphates by the salvage enzymes. Finally, phosphorolysis of brain nucleosides generates pentose phosphates, which are utilised for nucleoside interconversion, 5-phosphoribosyl-1-pyrophosphate synthesis, and energy repletion. This review focuses on these aspects of brain nucleoside metabolism, with the aim of giving a comprehensive picture of the metabolic network of nucleosides in normoxic conditions, with some hints on the derangements in anoxic/ischemic conditions.

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

“…Both enzymes are expressed in neurones and astrocytes, with similar levels of APRT, but greater expression of HPRT in neurones [80]; mutations in HPRT are responsible for Lesch-Nyhan disease [81]. Two further steps convert IMP to AMP, which can then be converted to ATP via adenylate kinases [68].…”

Anatomical Distribution of Nucleoside System in the Human Brain and Implications for Therapy

“…Nucleoside metabolic enzymes form a complex network, including several alternative metabolic pathways (Ipata et al 2011 ; (Fig. 29.1 ).…”

“…In the fi nal step of purine catabolism in the human brain, Xn is converted to uric acid (UA) by xanthine oxidase (XO). The following enzymes regulate the extracellular (EC) Ado concentration: ecto-5 ¢ -nucleotidase (eN), ectoadenosine kinase (ecto-ADK), and ecto-adenosine deaminase (ecto-ADA) (Fernández et al 2010 ;Firestein et al 1999 ;Ipata et al 2011 ;Yegutkin 2008 ;Zimmermann 1996 ) (Fig. 29.1 ).…”

The Antiepileptic Potential of Nucleosides

“…De novo synthesis of nucleosides is limited in the adult brain [39]. Therefore, nucleoside transport into the brain via the blood-brain barrier and a salvage mechanism supply brain cells with nucleosides [40,41]. The nucleosides may be metabolized intracellularly or extracellularly ( Fig.…”

“…The nucleosides may be metabolized intracellularly or extracellularly ( Fig. 1) [40][41][42] and transported via the nucleoside transporters expressed in brain cells (Table 1) [40,41,43]. There is considerable evidence for neuromodulatory functions of nucleosides.…”