Title |
Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors
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Published in |
Frontiers in Pharmacology, February 2017
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DOI | 10.3389/fphar.2017.00054 |
Pubmed ID | |
Authors |
Sang-Yong Lee, Soumya Sarkar, Sanjay Bhattarai, Vigneshwaran Namasivayam, Steven De Jonghe, Holger Stephan, Piet Herdewijn, Ali El-Tayeb, Christa E. Müller |
Abstract |
Nucleotide pyrophosphatase/phosphodiesterase type 1 (NPP1) is a membrane glycoprotein involved in the hydrolysis of extracellular nucleotides. Its major substrate is ATP which is converted to AMP and diphosphate. NPP1 was proposed as a new therapeutic target in brain cancer and immuno-oncology. Several NPP1 inhibitors have been reported to date, most of which were evaluated vs. the artificial substrate p-nitrophenyl 5'-thymidine monophosphate (p-Nph-5'-TMP). Recently, we observed large discrepancies in inhibitory potencies for a class of competitive NPP1 inhibitors when tested vs. the artificial substrate p-Nph-5'-TMP as compared to the natural substrate ATP. Therefore, the goal of the present study was to investigate whether inhibitors of human NPP1 generally display substrate-dependent inhibitory potency. Systematic evaluation of nucleotidic as well as non-nucleotidic NPP1 inhibitors revealed significant differences in determined Ki values for competitive, but not for non- and un-competitive inhibitors when tested vs. the frequently used artificial substrate p-Nph-5'-TMP as compared to ATP. Allosteric modulation of NPP1 by p-Nph-5'-TMP may explain these discrepancies. Results obtained using the AMP derivative p-nitrophenyl 5'-adenosine monophosphate (p-Nph-5'-AMP) as an alternative artificial substrate correlated much better with those employing the natural substrate ATP. |
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