Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase

Abstract

Choline is an essential nutrient for all living cells and is produced extracellularly by sequential degradation of phosphatidylcholine (PC). However, little is known about how choline is produced extracellularly. Here, we report that ENPP6, a choline-specific phosphodiesterase, hydrolyzes glycerophosphocholine (GPC), a degradation product of PC, as a physiological substrate and participates in choline metabolism. ENPP6 is highly expressed in liver sinusoidal endothelial cells and developing oligodendrocytes, which actively incorporate choline and synthesize PC. ENPP6-deficient mice exhibited fatty liver and hypomyelination, well known choline-deficient phenotypes. The choline moiety of GPC was incorporated into PC in an ENPP6-dependent manner both in vivo and in vitro. The crystal structure of ENPP6 in complex with phosphocholine revealed that the choline moiety of the phosphocholine is recognized by a choline-binding pocket formed by conserved aromatic and acidic residues. The present study provides the molecular basis for ENPP6-mediated choline metabolism at atomic, cellular and tissue levels.

Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders

“…In a follow-up study, the ecto-enzyme Enpp6 was also identified as an encoding marker of newly forming OLs during adult myelination [29]. Mechanistically, Enpp6, as phosphodiesterase, likely has a role in lipid metabolism during myelin formation [30] and might be required to initiate myelination rapidly in response to differentiation-inducing signals. Consequently, it has been shown that conditional deletion of Myrf in NG2-glia prevents the development of new Enpp6 + OLs which leads to impaired learning [29].…”

A key tyrosine substitution restricts nucleotide hydrolysis by the ectoenzyme NPP5

“…1A). The crystal structures of NPP1 [3,4], NPP2 [7,8], NPP4 [6], NPP6 [9], and NPP7 [10] are known, and the secondary structure elements are well-conserved within the catalytic domain (Fig. This a-b-a fold classifies the protein into the alkaline phosphatase superfamily (CATH ID: 3.40.720.10).…”

“…NPP1 is located on the surface of osteoblasts and chondrocytes where it cleaves NTPs to generate pyrophosphate, an inhibitor of bone mineralization [3,4]. NPP6 participates in choline metabolism, with glycerophosphocholine as the proposed substrate [9], whereas NPP7 (alkaline sphingomyelinase) digests dietary sphingomyelin in the intestines [10]. NPP4 is present on brain vascular endothelium and participates in hemostasis by converting diadenosine triphosphate to ADP, which induces platelet aggregation [6].…”

Ulk4 deficiency leads to hypomyelination in mice

“…Mog is located on the surface of oligodendrocytes and myelin sheaths (Brunner, Lassmann, Waehneldt, Matthieu, & Linington, ). Enpp6 is required for the development of myelin sheath (Morita et al, ). Mobp plays a role in myelin compaction or stabilization (Montague, McCallion, Davies, & Griffiths, ).…”