Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity

Abstract

Ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family members (ENPP1–7) have been implicated in key biological and pathophysiological processes, including nucleotide and phospholipid signaling, bone mineralization, fibrotic diseases, and tumor-associated immune cell infiltration. ENPPs are single-pass transmembrane ecto-enzymes, with notable exceptions of ENPP2 (Autotaxin) and ENNP6, which are secreted and glycosylphosphatidylinositol (GPI)-anchored, respectively. ENNP1 and ENNP2 are the best characterized and functionally the most interesting members. Here, we review the structural features of ENPP1–7 to understand how they evolved to accommodate specific substrates and mediate different biological activities. ENPPs are defined by a conserved phosphodiesterase (PDE) domain. In ENPP1–3, the PDE domain is flanked by two N-terminal somatomedin B-like domains and a C-terminal inactive nuclease domain that confers structural stability, whereas ENPP4–7 only possess the PDE domain. Structural differences in the substrate-binding site endow each protein with unique characteristics. Thus, ENPP1, ENPP3, ENPP4, and ENPP5 hydrolyze nucleotides, whereas ENPP2, ENPP6, and ENNP7 evolved as phospholipases through adaptions in the catalytic domain. These adaptations explain the different biological and pathophysiological functions of individual members. Understanding the ENPP members as a whole advances our insights into common mechanisms, highlights their functional diversity, and helps to explore new biological roles.

Mechanosensitive Hydrolysis of ATP and ADP in Lamina Propria of the Murine Bladder by Membrane-Bound and Soluble Nucleotidases

“…ENPP3 also hydrolases ATP, but to a lesser degree than ENPP1. ENPP4 has been shown to degrade ATP in vitro , but the ATP hydrolysis rate by ENPP4 is negligible compared to that of ENPP1 ( Borza et al, 2021 ). Purine nucleotides are not preferred substrates for ENPP2,5,6, and 7 as these enzymes have evolved as phospholipases with phosphodiesterase activities ( Borza et al, 2021 ).…”

Mouse hybrid genome mediates diverse brain phenotypes with the specificity of reciprocal crosses

“…Our findings demonstrated the impact of cell‐type on the status of genomic imprinting in the brain. Regarding the functions and functional consequences of the genes: DUSP26 regulates intracellular signaling pathways and is heavily implicated in cancer 67 ; ENPP1 hydrolyses ATP and is mainly implicated in mineralization disorders and soft‐tissue calcification 68 ; NDUFS7 mediates mitochondrial electron transport and is involved in cancer 69 ; and PLCG1 regulates the dynamics of the actin cytoskeleton and is involved in kidney and brain development 70 . Moreover, knockout mice for all four genes are available in the International Mouse Strain Resource (http://www.findmice.org/index).…”

Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators

“…The diversity associated with the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family of enzymes has inspired extensive research into their independent pathophysiological functions. Of the seven structurally related enzymes, all of which elicit varying cell signaling responses, autotaxin (ATX, ENPP2) is unique in that it is the only non-membrane bound family member, 1 therefore representing an attractive and clinically relevant biomarker.…”