ectonucleotide pyrophosphatase/phosphodiesterase family member 2; E-NPP 2; autotaxin; extracellular lysophospholipase D; lysoPLD; phosphodiesterase 1 alpha (ENPP2, ATX, PDNP2)

Function: - hydrolyzes lysophospholipids to produce lysophosphatidic acid in extracellular fluids - major substrate is lysophosphatidylcholine - uses sphingosylphosphphorylcholine as a substrate producing sphingosine-1-phosphate, a modulator of cell motility - can hydrolyze, in vitro, bis-pNPP, to some extent pNP-TMP, & barely ATP - role in several motility- related processes including angiogenesis & neurite outgrowth - acts as an angiogenic factor by stimulating migration of smooth muscle cells & microtubule formation - stimulates migration of melanoma cells, probably via a pertussis toxin-sensitive G protein - may have a role in induction of parturition - possible involvement in cell proliferation & adipose tissue development - tumor cell motility-stimulating factor - N-glycosylation, but not furin-cleavage, plays a critical role on secretion & on lysoPLD activity (putative) 1-alkyl-sn-glycero-3-phosphoethanolamine + H₂O = 1-alkyl-sn-glycerol 3-phosphate + ethanolamine , Kinetic parameters: - KM=0.5 mM for 16:0-LPC (at pH 8.5) - KM=5.5 mM for pNP-TMP (at pH 8.5) - KM=11.3 mM for pNppp (isoform 1) - KM=5.7 mM for pNppp (isoform 2) - KM=19.8 mM for pNppp (isoform 3) - Vmax=1.9 nmol/min/ug enzyme with pNppp as substrate (isoform 1) - Vmax=0.67 nmol/min/ug enzyme with pNppp as substrate (isoform 2) - Vmax=1.6 nmol/min/ug enzyme with pNppp as substrate (isoform 3) - pH dependence: optimum pH - 9.0 (isoform 1) - 8.0 (isoform 3) - isoform 1 is less sensitive to pH - isoform 1, isoform 2 & isoform 3 all retain some activity at pH 9.5 - Temperature dependence: - isoform 1 & isoform 3 are active from 45-60 degrees C Cofactor: - binds 2 Zn⁺² per subunit (putative) - binds 1 Ca⁺² per subunit (putative) Inhibition: - inhibited by lysophosphatidic acid & sphingosine-1-phosphate - inhibited by EDTA & EGTA(probable) Structure: - belongs to the nucleotide pyrophosphatase/phosphodiesterase family - contains 2 SMB (somatomedin-B) domains - the active SMB domain may be permitted considerable disulfide bond heterogeneity or variability, thus two alternate disulfide patterns based on 3D structures are described with 1 disulfide bond conserved in both Compartment: - secreted into most body fluids including serum & CSF Alternative splicing: named isoforms=3 Expression: - predominantly expressed in brain, placenta, ovary, & small intestine - expressed in a number of carcinomas including a) hepatocellular carcinoma b) prostate carcinoma c) neuroblastoma d) non-small-cell lung cancer - present in body fluids such as plasma, cerebral spinal fluid (CSF), saliva, follicular fluid & amniotic fluids - not detected in leukocytes - isoform 1 is expressed at higher levels in peripheral tissues than in the central nervous system (CNS) - adipocytes only express isoform 1 - isoform 3 is expressed at higher levels in the brain than in peripheral tissues - up-regulated in massively obese subjects with glucose intolerance, & during adipogenesis

General

Ca+2 binding protein glycoprotein phosphodiesterase I/nucleotide pyrophosphatase or ectonucleotide pyrophosphatase/phosphodiesterase phosphodiesterase 1 (PDE1, calcium/calmodulin dependent phosphodiesterase, cyclic nucleotide phosphodiesterase [CNP] type 1) secreted protein

Properties

SIZE: entity length = 863 aa MW = 99 kD COMPARTMENT: extracellular compartment MOTIF: signal sequence {1-27} N-glycosylation site {N54} SMB 1 {55-98} MOTIF: cysteine residue {C59} MODIFICATION: cysteine residue {C76} cysteine residue {C59} MODIFICATION: cysteine residue {C63} cysteine residue {C63} MODIFICATION: cysteine residue {C59} cysteine residue {C63} MODIFICATION: cysteine residue {C94} cysteine residue {C74} MODIFICATION: cysteine residue {C87} cysteine residue {C74} MODIFICATION: cysteine residue {C76} cysteine residue {C76} MODIFICATION: cysteine residue {C59} cysteine residue {C76} MODIFICATION: cysteine residue {C74} cysteine residue {C80} MODIFICATION: cysteine residue {C86} cysteine residue {C86} MODIFICATION: cysteine residue {C80} cysteine residue {C87} MODIFICATION: cysteine residue {C74} cysteine residue {C87} MODIFICATION: cysteine residue {C94} cysteine residue {C94} MODIFICATION: cysteine residue {C63} cysteine residue {C94} MODIFICATION: cysteine residue {C87} SMB 2 {99-143} MOTIF: cysteine residue {C103} MODIFICATION: cysteine residue {C120} cysteine residue {C103} MODIFICATION: cysteine residue {C108} cysteine residue {C108} MODIFICATION: cysteine residue {C103} cysteine residue {C108} MODIFICATION: cysteine residue {C138} cysteine residue {C118} MODIFICATION: cysteine residue {C131} cysteine residue {C118} MODIFICATION: cysteine residue {C120} cysteine residue {C120} MODIFICATION: cysteine residue {C103} cysteine residue {C120} MODIFICATION: cysteine residue {C118} cysteine residue {C124} MODIFICATION: cysteine residue {C130} Cell attachment site {127-129} cysteine residue {C130} MODIFICATION: cysteine residue {C124} cysteine residue {C131} MODIFICATION: cysteine residue {C118} cysteine residue {C131} MODIFICATION: cysteine residue {C138} cysteine residue {C138} MODIFICATION: cysteine residue {C108} cysteine residue {C138} MODIFICATION: cysteine residue {C131} cysteine residue {C149} MODIFICATION: cysteine residue {C195} cysteine residue {C157} MODIFICATION: cysteine residue {C351} Zn+2-binding site SITE: 172-172 cysteine residue {C195} MODIFICATION: cysteine residue {C149} threonine residue {T210} Zn+2-binding site SITE: 210-210 Substrate binding {211-214} Substrate binding {244-255} Zn+2-binding site SITE: 312-312 Zn+2-binding site SITE: 316-316 cysteine residue {C351} MODIFICATION: cysteine residue {C157} Zn+2-binding site SITE: 359-359 Zn+2-binding site SITE: 360-360 cysteine residue {C367} MODIFICATION: cysteine residue {C469} N-glycosylation site {N411} cysteine residue {C414} MODIFICATION: cysteine residue {C806} cysteine residue {C469} MODIFICATION: cysteine residue {C367} Zn+2-binding site SITE: 475-475 N-glycosylation site {N525} Ca+2-binding site SITE: 740-740 Ca+2-binding site SITE: 744-744 Ca+2-binding site SITE: 746-746 Ca+2-binding site SITE: 748-748 cysteine residue {C806} MODIFICATION: cysteine residue {C414} N-glycosylation site {N807} secretion {830-851} lysine residue {853}

Database Correlations

OMIM 601060 UniProt Q13822 PFAM correlations Entrez Gene 5168 Kegg hsa:5168 ENZYME 3.1.4.39