Nucleotide Pyrophosphatases/Phosphodiesterases on the Move

Abstract

Nucleotide pyrophosphatases/phosphodiesterases (NPPs) release nucleoside 5'-monophosphates from nucleotides and their derivatives. They exist both as membrane proteins, with an extracellular active site, and as soluble proteins in body fluids. The only well-characterized NPPs are the mammalian ecto-enzymes NPP1 (PC-1), NPP2 (autotaxin) and NPP3 (B10; gp130(RB13-6)). These are modular proteins consisting of a short N-terminal intracellular domain, a single transmembrane domain, two somatomedin-B-like domains, a catalytic domain, and a C-terminal nuclease-like domain. The catalytic domain of NPPs is conserved from prokaryotes to mammals and shows remarkable structural and catalytic similarities with the catalytic domain of other phospho-/sulfo-coordinating enzymes such as alkaline phosphatases. Hydrolysis of pyrophosphate/phosphodiester bonds by NPPs occurs via a nucleotidylated threonine. NPPs are also known to auto(de)phosphorylate this active-site threonine, a process accounted for by an intrinsic phosphatase activity, with the phosphorylated enzyme representing the catalytic intermediate of the phosphatase reaction. NPP1-3 have been implicated in various processes, including bone mineralization, signaling by insulin and by nucleotides, and the differentiation and motility of cells. While it has been established that most of these biological effects of NPPs require a functional catalytic site, their physiological substrates remain to be identified.

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

“…Hence, E-NPP1 is implicated in a wide range of processes including nucleotide recycling, purinergic receptor signalling and ATP-mediated apoptosis. 26 To further elucidate the functional consequence of ENPP1 knockdown in GSCs, we tested the 2104 differentially regulated genes for enrichment in KEGG pathways using GSEA. Lists of the top enriched KEGG pathways (FDR q-valueo0.05) and of enriched genes are shown in Supplementary Table S2.…”

“…17 This membrane-bound enzyme has broad substrate specificity cleaving phosphodiester, pyrophosphate and phosphosulphate bonds of nucleotides and nucleotide derivatives. 26,32 Originally, E-NPP1 was discovered on the surface of mouse B-lymphocytes 33 and is expressed in a large variety of human tissues including brain. 26 Here we describe an elevated ENPP1 expression in GSCs compared with normal brain extracts and fNSCs.…”

Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

“…E-NPPs. These integral membrane glycoproteins cleave phosphodiester bonds from various nucleotides (i.e., ATP, NAD, ADP-ribose, Ap 4 A, deoxyATP), thereby releasing AMP (15). This NTPPH activity is commonly identified with the synthetic substrate, thymidine 5Ј-monophosphate p-nitrophenyl ester (TMP-PNP) ( Table 2).…”

“…Currently, 5 human genes are known to encode E-NPPs (15). The widespread NPP1 (PC-1) was first identified as a serologic marker of human lymphocytes (41).…”

“…The ttw phenotype results from a nonsense mutation in the gene encoding nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1), also known as plasma cell membrane glycoprotein 1 (PC-1) (14). This ectoenzyme generates ePPi from extracellular ATP (eATP) (see below) (15). Ossification of the posterior longitudinal ligament of the spine in humans involves a dysfunctional NPP1 (16).…”