Ectonucleotide

Ectonucleotide refers to a nucleotide located outside the cell, in the extracellular space or bound to the cell surface. In physiology, extracellular nucleotides such as ATP, ADP, UTP, and UDP function as signaling molecules that activate purinergic receptors (P2X ion channels and P2Y G protein–coupled receptors) on nearby cells. The term is often used in the context of ectonucleotidases, a family of enzymes that regulate the levels of these nucleotides at the cell surface.

Ectonucleotidases include the ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), which hydrolyze ATP and ADP to AMP; and the ecto-5'-nucleotidase (CD73), which converts AMP to adenosine. Other enzymes, such as ENPP family members, can hydrolyze nucleotides to nucleosides or to phosphates and nucleosides, depending on substrate and context. These enzymes are anchored to the plasma membrane with active sites facing outward, thereby shaping the extracellular nucleotide landscape.

Extracellular nucleotides and their metabolites play roles in thrombosis, vascular tone, inflammation, immune cell recruitment, and neurotransmission. ATP often has pro-inflammatory and pro-thrombotic effects, whereas adenosine generally exerts anti-inflammatory and tissue-protective actions. The balance between ATP/ADP and adenosine is controlled by ectonucleotidases and can be altered in disease states such as cancer, cardiovascular disease, and autoimmune disorders.

Because of their central role in purinergic signaling, ectonucleotidases are explored as therapeutic targets. Inhibitors or modulators of CD39, CD73, and related enzymes are studied for potential applications in cancer immunotherapy, thrombosis prevention, and inflammatory diseases. Research continues to map the distribution, regulation, and substrate specificity of ectonucleotidases across tissues.