Ectonucleoside triphosphate diphosphohydrolase 1, 2, and 3 (NTPDase 1, 2, 3) (NTPDase 1/2/3)

Ectonucleoside triphosphate diphosphohydrolases (NTPDases) 1, 2, and 3 are integral membrane proteins that regulate the concentration of extracellular nucleotides, a process central to purinergic signaling (UniProt P49961, Q9Y5L3, O75355). NTPDase1, commonly known as CD39, is the dominant isoform in the immune system and vasculature, where it hydrolyzes ATP and ADP into AMP (PubMed: 31075131). This enzymatic activity serves as a critical "immunological switch," as it depletes pro-inflammatory ATP and provides the substrate for CD73 to produce immunosuppressive adenosine (Nature Reviews Cancer: 10.1038/s41568-019-0143-x). NTPDase2 and NTPDase3 exhibit different substrate preferences—NTPDase2 primarily converts ATP to ADP, while NTPDase3 hydrolyzes both ATP and ADP—and are involved in regulating neurotransmission and vascular tone (NCBI Gene: 953, 954, 955). In the context of oncology, high expression of these enzymes, particularly CD39, by tumor cells and regulatory T cells contributes to an immunosuppressive tumor microenvironment that facilitates immune evasion (Journal for ImmunoTherapy of Cancer: 10.1136/jitc-2020-001044). Consequently, therapeutic inhibitors and monoclonal antibodies targeting these NTPDases are being developed to restore anti-tumor immune responses by maintaining extracellular ATP levels and preventing adenosine accumulation (ClinicalTrials.gov: NCT03884556, NCT04336098).

Other names

CD39CD39L1CD39L3ENTPD1ENTPD2ENTPD3ATPDaseApyrase

Inhibition of the enzymatic hydrolysis of extracellular ATP and ADP to AMP, thereby modulating the purinergic signaling balance between immunostimulatory ATP and immunosuppressive adenosine.