Alternative titles; symbols
HGNC Approved Gene Symbol: ENPP2
Cytogenetic location: 8q24.12 Genomic coordinates (GRCh38): 8:119,557,086-119,673,390 (from NCBI)
The bifunctional enzyme phosphodiesterase I (EC 3.1.4.1)/nucleotide pyrophosphatase (EC 3.6.1.9) was cloned from rat brain by Narita et al. (1994) and designated PDI-alpha. Kawagoe et al. (1995) obtained the human cDNA, which codes for a predicted 863-amino acid protein with 89% identity to the rat protein. Northern blot analysis detected a 3-kb transcript in brain, placenta, kidney, and lung. PDI-alpha is identical to autotaxin (ATX), a tumor cell motility-stimulating factor (Murata et al., 1994), except that PDI-alpha lacks 52 amino acids of ATX. Kawagoe et al. (1995) concluded that PDI-alpha and ATX are likely to be splice variants of the same gene. They obtained a genomic clone for the 5-prime end of the gene, which contained a variety of potential DNA-binding sites as well as intron 1.
Tokumura et al. (2002) purified lysophospholipase D (lysoPLD) from human plasma. Mass spectroscopy, sequence analysis, and biochemical characterization revealed that it is a soluble form of autotaxin/PDI-alpha. The full-length protein contains 863-amino acids, and it migrated as a single band at 110 kD by nonreducing SDS/PAGE. Reducing SDS/PAGE revealed bands at about 75 and 30 kD, suggesting that the 2 peptides become cross-linked via disulfide bridge(s).
Giganti et al. (2008) identified 3 splice variants of mouse and human ENPP2, which they called ATX-alpha, -beta, and -gamma. The deduced human proteins contain 915, 863, and 889 amino acids, respectively. Quantitative PCR detected total ATX expression in most human tissues examined, with highest levels in adipose and retina, followed by lung, adrenal gland, kidney, and brain. RT-PCR confirmed highest ATX-gamma expression in brain and predominant ATX-beta expression in peripheral tissues, whereas ATX-alpha showed relatively low expression in both central nervous system and peripheral tissues.
By biochemical analysis, Tokumura et al. (2002) determined that lysoPLD has a substrate preference for lysophosphatidylcholine, with the production of physiologically active lysophosphatidic acid. Activity was enhanced in the presence of Co(2+) and inhibited by both ATP and a synthetic substrate for nucleotide. Serum lysoPLD activity increased in normal pregnant women at the third trimester and was increased further in patients threatened with preterm delivery. Tokumura et al. (2002) concluded that lysoPLD may induce parturition.
Giganti et al. (2008) showed that the ATX-alpha, -beta and -gamma isoforms had phosphodiesterase activity following expression in COS or insect cells. Using a series of lysophosphatidylcholines bearing fatty acids of different length and degree of saturation, they found that the preferred substrate for all isoforms was lauroyl lysophosphatidylcholine, with a C12 chain length. The beta and gamma isoforms presented maximal activity at pH 8 and 9, respectively, whereas the alpha isoform was less sensitive to pH. Chelating agents, zinc, and manganese inhibited activity, and cobalt and nickel enhanced activity.
Giganti et al. (2008) determined that the ENPP2 gene contains 27 exons.
By fluorescence in situ hybridization, Kawagoe et al. (1995) mapped the PDNP2 gene to chromosome 8q24.1. By FISH, Piao et al. (1999) mapped the mouse homolog to chromosome 15D2, a region that shows conserved synteny with human 8q.
Giganti, A., Rodriguez, M., Fould, B., Moulharat, N., Coge, F., Chomarat, P., Galizzi, J.-P., Valet, P., Saulnier-Blache, J.-S., Boutin, J. A., Ferry, G. Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. J. Biol. Chem. 283: 7776-7789, 2008. [PubMed: 18175805] [Full Text: https://doi.org/10.1074/jbc.M708705200]
Kawagoe, H., Soma, O., Goji, J., Nishimura, N., Narita, M., Inazawa, J., Nakamura, H., Sano, K. Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2). Genomics 30: 380-384, 1995. [PubMed: 8586446] [Full Text: https://doi.org/10.1006/geno.1995.0036]
Murata, J., Lee, H. Y., Clair, T., Krutzsch, H. C., Arestad, A. A., Sobel, M. E., Liotta, L. A., Stracke, M. L. cDNA cloning of human tumor motility-stimulating protein, autotaxin, reveals a homology with phosphodiesterases. J. Biol. Chem. 269: 30479-30484, 1994. [PubMed: 7982964]
Narita, M., Goji, J., Nakamura, H., Sano, K. Molecular cloning, expression, and localization of a brain-specific phosphodiesterase I/nucleotide (PD-I-alpha) from rat brain. J. Biol. Chem. 269: 28235-28242, 1994. [PubMed: 7961762]
Piao, J.-H., Matsuda, Y., Nakamura, H., Sano, K. Assignment of Pdnp2, the gene encoding phosphodiesterase I/nucleotide pyrophosphatase 2, to mouse chromosome 15D2. Cytogenet. Cell Genet. 87: 172-174, 1999. [PubMed: 10702660] [Full Text: https://doi.org/10.1159/000015459]
Tokumura, A., Majima, E., Kariya, Y., Tominaga, K., Kogure, K., Yasuda, K., Fukuzawa, K. Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. J. Biol. Chem. 277: 39436-39442, 2002. [PubMed: 12176993] [Full Text: https://doi.org/10.1074/jbc.M205623200]