The Inside Story of Adenosine

Abstract

Several physiological functions of adenosine (Ado) appear to be mediated by four G protein-coupled Ado receptors. Ado is produced extracellularly from the catabolism of the excreted ATP, or intracellularly from AMP, and then released through its transporter. High level of intracellular Ado occurs only at low energy charge, as an intermediate of ATP breakdown, leading to hypoxanthine production. AMP, the direct precursor of Ado, is now considered as an important stress signal inside cell triggering metabolic regulation through activation of a specific AMP-dependent protein kinase. Intracellular Ado produced from AMP by allosterically regulated nucleotidases can be regarded as a stress signal as well. To study the receptor-independent effects of Ado, several experimental approaches have been proposed, such as inhibition or silencing of key enzymes of Ado metabolism, knockdown of Ado receptors in animals, the use of antagonists, or cell treatment with deoxyadenosine, which is substrate of the enzymes acting on Ado, but is unable to interact with Ado receptors. In this way, it was demonstrated that, among other functions, intracellular Ado modulates angiogenesis by regulating promoter methylation, induces hypothermia, promotes apoptosis in sympathetic neurons, and, in the case of oxygen and glucose deprivation, exerts a cytoprotective effect by replenishing the ATP pool.

Keywords: adenosine; adenosine deaminase; adenosine kinase; adenosine receptors; deoxyadenosine; energy repletion; transmethylation.

Figure 1

Interplay between internal and external Ado production. Ado originates intracellularly from AMP predominantly in case of low energy charge, and can be exported or deaminated. Extracellular Ado stemming from ATP breakdown may enter the cell and is readily phosphorylated by the low K_M adenosine kinase (AdoK). The high K_M adenosine deaminase (ADA) comes into play if Ado accumulates. 1: cytosolic 5′-nucleotidase I (cN-I); 2: AMP deaminase; 3: cytosolic 5′-nucleotidase II (cN-II); 4: purine nucleoside phosphorylase (PNP); 5: phosphoribomutase; 6: PRPP synthetase; 7: hypoxanthine guanine phosphoribosyltransferase (HPRT); 8: adenylate kinase; 9,11: ecto-nucleoside triphosphate diphosphohydrolase; 9: ecto-nucleotide pyrophosphatase/phosphodiesterase; 12: ecto-5′-nucleotidase.

Figure 2

Transmethylation pathway. S-Adenosylhomocysteine (SAH) is hydrolyzed to homocysteine and Ado by S-adenosylhomocysteine hydrolase (SAHH). 1: Methionine synthase. 2: Methionine adenosyl transferase catalyzes the formation of S-adenosylmethionine (SAM). SAM is the donor of methyl group in the transmethylation reactions catalyzed by methyltransferases (MethylT). X: acceptor (protein, DNA, RNA) of the methyl group. SAH is an inhibitor of MethylT (dashed line). Ado can exit or enter the cell through the ENT.

Figure 3

Schematic illustration of the uptake and utilization of (deoxy)Ado. The nucleoside enters the cell through ENT and is subjected to catabolic reactions. The destiny of the ribose moiety of the nucleoside is underlined. 1: Adenosine deaminase; 2: purine nucleoside phosphorylase; 3: phosphoribomutase; 4: deoxyRib-5-P aldolase; 5: aldehyde oxidase; 6: acetyl-CoA synthetase; 7: transketolase; 8: transaldolase. PPP: pentose phosphate pathway (non oxidative branch).