Ecto-nucleotidases and ecto-phosphatases

Ecto-nucleotidases and ecto-phosphatases are a heterogeneous group of enzymes anchored to the plasma membrane with their active sites facing the extracellular environment. This group includes the ecto-nucleoside triphosphate diphosphohydrolase (ENTPD) family (e.g., CD39), ecto-5'-nucleotidase (CD73), and ecto-nucleotide pyrophosphatase/phosphodiesterases (ENPPs) (Zimmermann et al., 2012, Purinergic Signalling). Their primary function is the sequential hydrolysis of extracellular nucleotides like ATP and ADP into AMP and subsequently into adenosine, thereby acting as a "purinergic switch" from a pro-inflammatory to an immunosuppressive state (Allard et al., 2017, Immunological Reviews). In oncology, these enzymes are frequently overexpressed by tumor and stromal cells to suppress the anti-tumor immune response by generating high local concentrations of adenosine (Smyth MJ, et al., 2019, Trends in Cancer). Beyond the immune system, members like tissue-nonspecific alkaline phosphatase (TNAP) and ENPP1 are vital for regulating bone mineralization and preventing vascular calcification. Therapeutic targeting of these enzymes, particularly CD39 and CD73, is a major area of development in cancer immunotherapy, utilizing monoclonal antibodies and small molecules to enhance the efficacy of existing checkpoint inhibitors (Antonioli et al., 2013, Nature Reviews Cancer).

Other names

Ecto-nucleoside triphosphate diphosphohydrolasesEcto-nucleotide pyrophosphatasesSurface-bound phosphatasesPurinergic enzymesENTPDasesENPPs

Inhibition of extracellular nucleotide hydrolysis to modulate purinergic signaling, specifically to decrease immunosuppressive adenosine levels or manage phosphate-related metabolic disorders.