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
  • hepatocellular carcinoma
  • prostate carcinoma
  • neuroblastoma
  • 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

More general terms

• phosphodiesterase 1
• glycoprotein
• phosphodiesterase I/nucleotide pyrophosphatase
• secreted protein
• Ca+2 binding protein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5168
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5168
• OMIM: https://mirror.omim.org/entry/601060
• UniProt: http://www.uniprot.org/uniprot/Q13822.html