Adenosine deaminase functions in the purine metabolism and salvage pathways, specifically catalyzing the irreversible deamination of adenosine and deoxyadenosine into inosine and deoxyinosine respectively. Inosine is deribosylated producing hypoxanthine, which can be irreversibly degraded into uric acid, or be reused in nucleotide salvage. Due to the high mitotic and apoptotic activity of lymphocytes undergoing development and selection, ADA is essential for the metabolic maintenance of the immune system. ADA deficiency is the second most common cause of severe combined immunodeficiency.
Loss of ADA function leads to the abnormal buildup of deoxyadenosine, and consequently dATP buildup, which is cytotoxic to developing lymphocytes. dATP buildup inhibits ribonucleotide reductase, therefore, it disrupts the reduction of ribonucleotides into 2’-deoxyribonucleotide precursors that are required for DNA synthesis. dATP buildup has also been shown to initiate the apoptotic cascade in cells, by inducing cytochrome c release from mitochondria. Additionally, elevated adenosine and dATP levels inhibit S-adenosylhomocysteine hydrolase (SAHh). Normally considered as a regulator in the methyl cycle, SAHh reversibly, albeit favorably, hydrolyzes SAH into adenosine and homocysteine. The resulting buildup of SAH inhibits S-adenosylmethionine dependent methylation reactions, compromising cell viability. Adenosine toxicity has been shown to interfere with mature T-cell receptor signaling and activation.