Ectonucleotidases

Ectonucleotidases are a family of cell-surface enzymes that catalyze the breakdown of extracellular nucleotides, notably ATP, ADP, and AMP, into nucleosides such as adenosine. By controlling the balance of signaling nucleotides and nucleosides outside cells, they regulate purinergic signaling through P2 receptor (for ATP/ADP) and P1 receptor (for adenosine) pathways, thereby influencing inflammation, thrombosis, vascular tone, and immune cell function.

The major ectonucleotidase families include the E-NTPDases, such as CD39 (ENTPD1), which hydrolyze ATP and ADP to AMP; the ecto-5'-nucleotidase CD73 (NT5E), which converts AMP to adenosine; and the ectonucleotide pyrophosphatases/phosphodiesterases (ENPP family), which have diverse substrate specificities. Together, these enzymes regulate the local concentration of pro-inflammatory nucleotides and the immunosuppressive adenosine that can accumulate in tissues. Ectonucleotidases are expressed on various cell types, including endothelial cells, dendritic cells, T and B cells, macrophages, and astrocytes, and can be shed into soluble form under certain conditions.

Physiological and pathological relevance is broad. By generating adenosine, ectonucleotidases can dampen excessive inflammation and modulate tissue protection during ischemia, but in the tumor microenvironment, high CD39/CD73 activity can promote immune evasion by creating adenosine-rich, immunosuppressive conditions. As such, ectonucleotidases are explored as therapeutic targets to modulate immune responses, inflammation, and cancer progression, or to protect tissues from ischemic injury. Measurements typically assess ATPase, ADPase, and 5'-nucleotidase activities.