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Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors

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. Seve...

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Autores principales: Lee, Sang-Yong, Sarkar, Soumya, Bhattarai, Sanjay, Namasivayam, Vigneshwaran, De Jonghe, Steven, Stephan, Holger, Herdewijn, Piet, El-Tayeb, Ali, Müller, Christa E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309242/
https://www.ncbi.nlm.nih.gov/pubmed/28261095
http://dx.doi.org/10.3389/fphar.2017.00054
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author Lee, Sang-Yong
Sarkar, Soumya
Bhattarai, Sanjay
Namasivayam, Vigneshwaran
De Jonghe, Steven
Stephan, Holger
Herdewijn, Piet
El-Tayeb, Ali
Müller, Christa E.
author_facet Lee, Sang-Yong
Sarkar, Soumya
Bhattarai, Sanjay
Namasivayam, Vigneshwaran
De Jonghe, Steven
Stephan, Holger
Herdewijn, Piet
El-Tayeb, Ali
Müller, Christa E.
author_sort Lee, Sang-Yong
collection PubMed
description 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 K(i) 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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spelling pubmed-53092422017-03-03 Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors Lee, Sang-Yong Sarkar, Soumya Bhattarai, Sanjay Namasivayam, Vigneshwaran De Jonghe, Steven Stephan, Holger Herdewijn, Piet El-Tayeb, Ali Müller, Christa E. Front Pharmacol Pharmacology 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 K(i) 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. Frontiers Media S.A. 2017-02-15 /pmc/articles/PMC5309242/ /pubmed/28261095 http://dx.doi.org/10.3389/fphar.2017.00054 Text en Copyright © 2017 Lee, Sarkar, Bhattarai, Namasivayam, De Jonghe, Stephan, Herdewijn, El-Tayeb and Müller. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Lee, Sang-Yong
Sarkar, Soumya
Bhattarai, Sanjay
Namasivayam, Vigneshwaran
De Jonghe, Steven
Stephan, Holger
Herdewijn, Piet
El-Tayeb, Ali
Müller, Christa E.
Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors
title Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors
title_full Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors
title_fullStr Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors
title_full_unstemmed Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors
title_short Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors
title_sort substrate-dependence of competitive nucleotide pyrophosphatase/phosphodiesterase1 (npp1) inhibitors
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309242/
https://www.ncbi.nlm.nih.gov/pubmed/28261095
http://dx.doi.org/10.3389/fphar.2017.00054
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