Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 8 (5), 823-840
eCollection

Nucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1) and Its Inhibitors

Affiliations
Review

Nucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1) and Its Inhibitors

Sang-Yong Lee et al. Medchemcomm.

Abstract

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1, EC 3.1.4.1) is a metalloenzyme that belongs to the NPP family, which comprises seven subtypes (NPP1-7). NPP1 hydrolyzes a wide range of phosphodiester bonds, e.g. in nucleoside triphosphates, (cyclic) dinucleotides, and nucleotide sugars yielding nucleoside 5'-monophosphates as products. Its main substrate is ATP which is cleaved to AMP and diphosphate. The enzyme is involved in various biological processes including bone mineralization, soft-tissue calcification, insulin receptor signalling, cancer cell proliferation and immune modulation. Therefore, NPP1 inhibitors have potential as novel drugs, e.g. for (immuno)oncology. In the last two decades several inhibitors of NPP1 derived from nucleotide- or non-nucleotide scaffolds have been developed. The most potent and selective NPP1-inhibitory substrate analog is adenosine 5'-α,β-methylene-γ-thiotriphosphate (Ki = 20 nM vs. p-Nph-5'-TMP, human membrane-bound NPP1). Non-nucleotide-derived NPP1 inhibitors comprise polysulfonates, polysaccharides, polyoxometalates and small heterocyclic compounds. The polyoxometalate [TiW11CoO40]8- (PSB-POM141) is the most potent and selective NPP1 inhibitor described to date (Ki = 1.46 nM vs. ATP, human soluble NPP1); it displays an allosteric mechanism of inhibition and represents a useful pharmacological tool for evaluating the potential of NPP1 as a novel drug target.

Figures

Fig. 1
Fig. 1. Metabolism of nucleotides by ecto-nucleotidases (modified from Zimmermann6). NTPDases, ecto-nucleoside triphosphate diphosphohydrolases; NPPs, ecto-nucleotide pyrophosphatases/phosphodiesterases; APs, alkaline phosphatases; eN, ecto-5′-nucleotidase (CD73); NTP, nucleoside triphosphate; NDP, nucleoside diphosphate; NMP, nucleoside monophosphate; Nuc, nucleoside.
Fig. 2
Fig. 2. Structure of the NPP1 dimer, modified from Stefan et al.
Fig. 3
Fig. 3. Natural substrates of NPP1. The site of hydrolysis is marked with a dashed red line.
Fig. 4
Fig. 4. 3′,3′′-Bridged cyclic dinucleotides which are not hydrolyzed by NPP1.
Fig. 5
Fig. 5. Artificial substrates of NPP1. The site of hydrolysis is marked with a dashed red line.
Fig. 6
Fig. 6. Inhibitors of NPP1 with nucleotide structure.
Fig. 7
Fig. 7. A series of non-nucleotidic inhibitors of NPP1.
Fig. 8
Fig. 8. Hypothetical model of allosteric binding of p-Nph-5′-TMP. The artificial substrate p-Nph-5′-TMP acts as an allosteric modulator in addition to being a substrate.
Fig. 9
Fig. 9. Physiological role of NPP1 in bone mineralization and soft-tissue calcification, modified from Stefan et al. Red minus: negative feedback of diphosphate (PPi).
Fig. 10
Fig. 10. The calcium pyrophosphate dihydrate deposition (CPPD) disease by increased expression of NPP1 in the condrocytes, modified from Stefan et al.
Fig. 11
Fig. 11. Binding of NPP1 to the insulin receptor, modified from Abate et al.
Fig. 12
Fig. 12. NPP1 inhibitors for the potential treatment of (brain) cancer. CD73, ecto-5′-nucleotidase; Ado, adenosine; NKT cells, natural killer cells; DCs, dendritic cells; Treg cells, regulatory T cells (CD4+); NLRP3 inflammasome, N[combining low line]ACHT, L[combining low line]R[combining low line]R and P[combining low line]YD domains-containing protein 3[combining low line].
None
Sang-Yong Lee
None
Christa E. Müller

Similar articles

See all similar articles

Cited by 5 articles

Feedback