Figure 3.

Adenosine and inosine pathways in hypoxic conditions (stress). During “cellular stress” conditions (e.g., hypoxia) the production of adenosine increases. Ecto and endo 5′NT enzymes mainly contribute to the production of adenosine in cells. The rate of SAH hydrolysis does not increase much (1.5-fold). When adenosine levels increase, adenosine deamination predominates and inosine reaches high concentration inside the cell. It is then shunted into the extracellular space by bidirectional equilibrative nucleoside transporters and interstitial levels of inosine can rise to greater than 1 mM. An array of evidence now suggests that under hypoxic conditions the phosphorylated ribose moiety of inosine is used for energy repletion through anaerobic glycolysis as an alternative or complementary to glucose. Inosine can generate ATP through the hypoxanthine-IMP-AMP pathway or through the anaerobic pentose pathway (Ribose1P). Hypoxanthine is rephosphorylated to inosine monophosphate using phosphoribosyl pyrophosphate (PRPP), leading to IMP and further AMP. At pH 7.4 ribose-1-phosphates can be converted to ribose-5-phosphate which rebuilds the purine ring system and can restore ATP via the anaerobic pentose pathway.