Ectonucleotidases consist of families of nucleotide metabolizing enzymes that are expressed on the plasma membrane and have externally oriented active sites. These ectoenzymes operate in concert or consecutively and metabolize nucleotides to the respective nucleoside analogs. They have the potential to decrease extracellular concentrations of nucleotides and to generate nucleosides. The relative contribution of the distinct enzymes to the modulation of purinergic signaling may depend on the availability and preference of substrates and on cell and tissue distribution.
Ectonucleotidases modulate P2-receptor-mediated signaling. Alterations in extracellular nucleotide levels can increase or decrease P2 activity or lead to P2 receptor desensitization. Desensitization of P2 receptors is dose dependent. In vitro the desensitization of anion secretion responses requires 10-min preincubations with the P2Y2 receptor agonist UTP. Recovery from UTP or ATP-induced desensitization can either be rapid (<10 min) at preincubation concentrations of approximately 2 µM or requires progressively longer time periods at higher concentrations. Furthermore, generation of extracellular adenosine not only abrogates nucleotide-mediated effects but also activates adenosine receptors, often with opposing (patho-) physiological effects.
Classification
There are four major families of ectonucleotidases in the liver microenvironment namely CD39/NTPDases (ecto-nucleotide triphosphate diphosphohydrolases), Nucleotide pyrophosphatase/phosphodiesterase (NPP)-type ecto-phosphodiesterases, alkaline phosphatases and ecto-5’-nucleotidases/CD73
Functions
Ectonucleotidases also produce the key molecules for purine salvage and consequent replenishment of ATP stores within multiple cell types. Indeed, although nucleotides do not appear to be taken up by cells, dephosphorylated nucleoside derivatives interact with several specific transporters to enable intracellular uptake via membrane passage.
Adenosine generation
The first step in the production of adenosine, involves the conversion of ATP/ADP to AMP. It is carried out by ENTPD1, also known as CD39. The second step involves the conversion of AMP to adenosine. It is carried out by NT5E, also known as CD73.[1]
References
- ^ Eltzschig, Holger K. (June 2013). "Attenuating myocardial ischemia by targeting A2B adenosine receptors". Trends in Molecular Medicine. 19 (6): 345–354. doi:10.1016/j.molmed.2013.02.005.
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