Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the ecto-nucleoside triphosphate diphosphohydrolase (eNTPDase) family exhibit distinctive substrate specificities, but how such specificities are achieved by enzymes with identical putative catalytic domains is unknown. Previously we showed that H59G substitution changes CD39 from an apyrase to an adenosine diphosphatase (ADPase) in a manner that depends on intact associations of both transmembrane domains with the membrane. Here we show that the extracellular domain of CD39L1 ecto-adenosine triphosphatase (ecto-ATPase) has the same 3:1 ATP:ADP hydrolysis ratio as the extracellular domain of CD39, suggesting that the transmembrane domains are required to confer the native substrate specificities on each enzyme. As in CD39, H50G substitution has little effect on the activity of the CD39L1 extracellular domain or solubilized monomers. However, H50G substitution diminishes both ATPase and ADPase activities of native CD39L1, in contrast to its selective effect on ATPase activity in CD39, suggesting that the transmembrane domains confer different ADP hydrolysis mechanisms on CD39 and CD39L1. We then show that the transmembrane domains of CD39L1 can substitute for those of CD39 in conferring native CD39 substrate specificity and regulation of H59 but that the transmembrane domains of CD39 confer neither CD39 nor CD39L1 properties on the CD39L1 extracellular domain. These results suggest that non-apyrase conserved region residues in the extracellular domain contain the information specifying CD39 native properties but have a nonspecific requirement for two transmembrane domains to manifest the information.
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PMID:Transmembrane domains confer different substrate specificities and adenosine diphosphate hydrolysis mechanisms on CD39, CD39L1, and chimeras. 1182 41

Transplantation results in exposure of the graft vasculature to warm and cold ischemia, followed by perfusion by circulating blood constituents and obligatory oxidant stress. Further graft injury occurs as consequences of acute humoral cellular rejection or chronic transplant vasculopathy, or both. Extracellular nucleotide stimulation of purinergic type 2 (P2) receptors are key components of platelet, endothelial cell (EC), and leukocyte activation resulting in vascular thrombosis and inflammation in vivo. CD39, the prototype nucleoside triphosphate diphosphohydrolase (NTPDase-1) is highly expressed on endothelium; in contrast, CD39L1/NTPDase-2 (a preferential adenosine triphosphatase [ATPase]) is found on vascular adventitial cells. Both ectoenzymes influence thrombogenesis by the regulated hydrolysis of extracellular nucleotides that differentially regulate P2-receptor activity and function in platelets and vascular cells. The intracytoplasmic domains of NTPDase-1 may also independently influence cellular activation and proliferation. NTPDase activity is substantively lost in the vasculature of injured or rejected grafts. A role for NTPDase-1 in thromboregulation has been validated by generation of mutant mice either null for cd39 or overexpressing human CD39. Administration of soluble NTPDase or induction of CD39 by adenoviral vectors, or both, are also of benefit in several models of transplantation. Administration of soluble CD39 or targeted expression may have future therapeutic application in transplantation-associated and other vascular diseases.
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PMID:Ectonucleotidases of CD39 family modulate vascular inflammation and thrombosis in transplantation. 1585 25