The GDA1_CD39 superfamily: NTPDases with diverse functions

Abstract

The first comprehensive review of the ubiquitous "ecto-ATPases" by Plesner was published in 1995. A year later, a lymphoid cell activation antigen, CD39, that had been cloned previously, was shown to be an ecto-ATPase. A family of proteins, related to CD39 and a yeast GDPase, all containing the canonical apyrase conserved regions in their polypeptides, soon started to expand. They are now recognized as members of the GDA1_CD39 protein family. Because proteins in this family hydrolyze nucleoside triphosphates and diphosphates, a unifying nomenclature, nucleoside triphosphate diphopshohydrolases (NTPDases), was established in 2000. Membrane-bound NTPDases are either located on the cell surface or membranes of intracellular organelles. Soluble NTPDases exist in the cytosol and may be secreted. In the last 15 years, molecular cloning and functional expression have facilitated biochemical characterization of NTPDases of many organisms, culminating in the recent structural determination of the ecto-domain of a mammalian cell surface NTPDase and a bacterial NTPDase. The first goal of this review is to summarize the biochemical, mutagenesis, and structural studies of the NTPDases. Because of their ability in hydrolyzing extracellular nucleotides, the mammalian cell surface NTPDases (the ecto-NTPDases) which regulate purinergic signaling have received the most attention. Less appreciated are the functions of intracellular NTPDases and NTPDases of other organisms, e.g., bacteria, parasites, Drosophila, plants, etc. The second goal of this review is to summarize recent findings which demonstrate the involvement of the NTPDases in multiple and diverse physiological processes: pathogen-host interaction, plant growth, eukaryote cell protein and lipid glycosylation, eye development, and oncogenesis.

Expression of mediators of purinergic signaling in human liver cell lines

“…For instance, purinergic signals regulate proliferation [12][13][14] and glucose release [15] in hepatocytes; secretion [16,17], proliferation [18], and mechanosensation [19] in cholangiocytes; and fibrogenic activity [20,21] and properties in HSC [22,23]. Of note, the purinergic signaling system is quite diverse, including multiple subtypes of G proteincoupled receptors for adenosine P1 receptors [24] and nucleotide P2Y receptors [25], nucleotide P2X ligand-gated ion channels [26], and a variety of plasma membrane-bound ecto-enzymes that regulate extracellular nucleotide/ nucleoside levels, namely ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases) [27,28], CD73/ecto-5′-nucleotidase [29,30], and tissue-non-specific alkaline phosphatase (TNAP) [31]. Thus, there is tremendous, almost overwhelming, complexity both in the relevant cell types and purinergic signaling systems relevant to liver physiology and disease [32].…”

Rat submandibular glands secrete nanovesicles with NTPDase and 5′-nucleotidase activities

“…6a, b shows exponential fitting of dPi/dt versus time, to obtain the initial activities (A i ), final activities (A f ), and time to reach 50 % of the fall (T 1/2 ). As proposed above, two functional components can be identified in the absence of Con-A, (a) an unstable initial ATPase activity ([A i -A f ]), progressively reduced during the hydrolysis reaction and not affected by NaN 3 , representing approximately 60 % of the total activity and consistent with NTPDase2 and (2) a stable ATPase activity (A f ) inhibited ∼50 % by N 3 Na. T 1/2 was around 1 min in both conditions, indicating that the inhibitor had no significant effect on inactivation mechanism.…”

“…Data are mean±SEM, n=3 NTPDase2 and NTPDase3 and markedly lower than the one reported for NTPDase1. Sodium azide (NaN 3 ) is known to inhibit NTPDase1, NTPDase3, and NTPDase8 to variable extents but not NTPDase2 [3]. Figure 6a shows Pi production by microsomes incubated with 3 mM ATP in the absence or presence of 10 mM NaN 3 .…”

“…Sodium azide (NaN 3 ) is known to inhibit NTPDase1, NTPDase3, and NTPDase8 to variable extents but not NTPDase2 [3]. Figure 6a shows Pi production by microsomes incubated with 3 mM ATP in the absence or presence of 10 mM NaN 3 . From the relation "[Pi]/initial [ATP]" at the end of the experiment, we estimated ATP hydrolysis that was always <10 %.…”

“…The most important family of ectonucleotidases that hydrolyses these molecules belongs to the ectonucleoside triphosphate diphosphohydrolase (ENTPDase) family [1,2]. Eight members of this family have been identified, which are either located at the plasma membrane (PM) and/or associated with intracellular membranes [3,4]. NTPDase1, NTPDase2, NTPDase3, and NTPDase8 have their catalytic site facing the extracellular environment where they hydrolyse nucleoside triphosphates (NTP) and nucleoside diphosphates (NDP), including ATP and ADP, respectively.…”