Ectonucleotide pyrophosphatase/phosphodiesterase 1 explained

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (PC-1, CD203a) is an enzyme that in humans is encoded by the ENPP1 gene.^{[1] [2] [3]}

Structure

This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits.

Function

ENPP1 has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars. ENPP1 protein may function to hydrolyze nucleoside 5′-triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates.

The main substrate of ENNP1 is adenosine triphosphate (ATP), which is cleaved into adenosine monophosphate (AMP) and diphosphate.^[4] Another notable nucleotide substrate is nicotinamide adenine dinucleotide (NAD+) which can be hydrolyzed to produce AMP. ADPR can also be hydrolyzed by ENNP1 to produce AMP.^[5]

Clinical significance

Mutations in this gene have been associated with Generalized arterial calcification of infancy, ossification of the posterior longitudinal ligament of the spine (OPLL), Hypophosphatemic rickets autosomal recessive 2 (ARHR2), and insulin resistance.^[2]

In a tumor microenvironment, AMP generated by ENNP1 can lead to production of adenosine, which suppresses the anti-cancer function of the immune system.^{[6] [7]}

Interactions

Ectonucleotide pyrophosphatase/phosphodiesterase 1 has been shown to interact with Insulin receptor.^[8]

See also

• Nucleotide pyrophosphatase/phosphodiesterase

Further reading

• Abate N, Chandalia M, Di Paola R, Foster DW, Grundy SM, Trischitta V . 8907895 . Mechanisms of disease: Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors . Nature Clinical Practice Endocrinology & Metabolism . 2 . 12 . 694–701 . 2007 . 17143316 . 10.1038/ncpendmet0367 .
• Bacci S, De Cosmo S, Prudente S, Trischitta V . 13172655 . ENPP1 gene, insulin resistance and related clinical outcomes . Current Opinion in Clinical Nutrition and Metabolic Care . 10 . 4 . 403–9 . 2007 . 17563456 . 10.1097/MCO.0b013e3281e386c9 .
• Fadini GP, Pauletto P, Avogaro A, Rattazzi M . The good and the bad in the link between insulin resistance and vascular calcification . Atherosclerosis . 193 . 2 . 241–4 . 2007 . 17606264 . 10.1016/j.atherosclerosis.2007.05.015 .
• Buckley MF, Loveland KA, McKinstry WJ, Garson OM, Goding JW . Plasma cell membrane glycoprotein PC-1. cDNA cloning of the human molecule, amino acid sequence, and chromosomal location . J. Biol. Chem. . 265 . 29 . 17506–11 . 1990 . 10.1016/S0021-9258(18)38193-6 . 2211644 . free .
• Belli SI, Mercuri FA, Sali A, Goding JW . Autophosphorylation of PC-1 (alkaline phosphodiesterase I/nucleotide pyrophosphatase) and analysis of the active site . Eur. J. Biochem. . 228 . 3 . 669–76 . 1995 . 7737162 . 10.1111/j.1432-1033.1995.tb20308.x .
• Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, Spencer S, Grupe A, Henzel W, Stewart TA . 4359358 . Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus . Nature . 373 . 6513 . 448–51 . 1995 . 7830796 . 10.1038/373448a0 . 1995Natur.373..448M .
• Belli SI, Goding JW . Biochemical characterization of human PC-1, an enzyme possessing alkaline phosphodiesterase I and nucleotide pyrophosphatase activities . Eur. J. Biochem. . 226 . 2 . 433–43 . 1995 . 8001561 . 10.1111/j.1432-1033.1994.tb20068.x . free .
• Huang R, Rosenbach M, Vaughn R, Provvedini D, Rebbe N, Hickman S, Goding J, Terkeltaub R . Expression of the murine plasma cell nucleotide pyrophosphohydrolase PC-1 is shared by human liver, bone, and cartilage cells. Regulation of PC-1 expression in osteosarcoma cells by transforming growth factor-beta . J. Clin. Invest. . 94 . 2 . 560–7 . 1994 . 8040311 . 296131 . 10.1172/JCI117370 .
• Jin-Hua P, Goding JW, Nakamura H, Sano K . Molecular cloning and chromosomal localization of PD-Ibeta (PDNP3), a new member of the human phosphodiesterase I genes . Genomics . 45 . 2 . 412–5 . 1998 . 9344668 . 10.1006/geno.1997.4949 .
• Nakamura I, Ikegawa S, Okawa A, Okuda S, Koshizuka Y, Kawaguchi H, Nakamura K, Koyama T, Goto S, Toguchida J, Matsushita M, Ochi T, Takaoka K, Nakamura Y . 238056 . Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL) . Hum. Genet. . 104 . 6 . 492–7 . 1999 . 10453738 . 10.1007/s004390050993 .
• Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, Ercolino T, Scarlato G, Iacoviello L, Vigneri R, Tassi V, Trischitta V . A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance . Diabetes . 48 . 9 . 1881–4 . 1999 . 10480624 . 10.2337/diabetes.48.9.1881 .
• Andoh K, Piao JH, Terashima K, Nakamura H, Sano K . Genomic structure and promoter analysis of the ecto-phosphodiesterase I gene (PDNP3) expressed in glial cells . Biochim. Biophys. Acta . 1446 . 3 . 213–24 . 1999 . 10524196 . 10.1016/s0167-4781(99)00090-1 .
• Maddux BA, Goldfine ID . Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit . Diabetes . 49 . 1 . 13–9 . 2000 . 10615944 . 10.2337/diabetes.49.1.13 . free .
• Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, Kalhoff H, Sano K, Boisvert WA, Superti-Furga A, Terkeltaub R . PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification . Am. J. Pathol. . 158 . 2 . 543–54 . 2001 . 11159191 . 1850320 . 10.1016/S0002-9440(10)63996-X .
• Frittitta L, Baratta R, Spampinato D, Di Paola R, Pizzuti A, Vigneri R, Trischitta V . The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance . J. Clin. Endocrinol. Metab. . 86 . 12 . 5888–91 . 2001 . 11739459 . 10.1210/jcem.86.12.8108 . free .
• Koshizuka Y, Kawaguchi H, Ogata N, Ikeda T, Mabuchi A, Seichi A, Nakamura Y, Nakamura K, Ikegawa S . Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine . J. Bone Miner. Res. . 17 . 1 . 138–44 . 2002 . 11771660 . 10.1359/jbmr.2002.17.1.138 . 20481601 . free .
• de Azevedo MJ, Dalmáz CA, Caramori ML, Pecis M, Esteves JF, Maia AL, Gross JL . ACE and PC-1 gene polymorphisms in normoalbuminuric Type 1 diabetic patients: a 10-year prospective study . J. Diabetes Complicat. . 16 . 4 . 255–62 . 2003 . 12126783 . 10.1016/s1056-8727(01)00185-4.
• De Cosmo S, Miscio G, Zucaro L, Margaglione M, Argiolas A, Thomas S, Piras G, Trevisan R, Perin PC, Bacci S, Frittitta L, Pizzuti A, Tassi V, Di Minno G, Viberti G, Trischitta V . The role of PC-1 and ACE genes in diabetic nephropathy in type 1 diabetic patients: evidence for a polygenic control of kidney disease progression . Nephrol. Dial. Transplant. . 17 . 8 . 1402–7 . 2003 . 12147786 . 10.1093/ndt/17.8.1402 . free .
• Jacobsen P, Grarup N, Tarnow L, Parving HH, Pedersen O . PC-1 amino acid variant (K121Q) has no impact on progression of diabetic nephropathy in type 1 diabetic patients . Nephrol. Dial. Transplant. . 17 . 8 . 1408–12 . 2003 . 12147787 . 10.1093/ndt/17.8.1408 . free .

Notes and References

1. Funakoshi I, Kato H, Horie K, Yano T, Hori Y, Kobayashi H, Inoue T, Suzuki H, Fukui S, Tsukahara M . Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase . Arch Biochem Biophys . 295 . 1 . 180–7 . June 1992 . 1315502 . 10.1016/0003-9861(92)90504-P .
2. Web site: Entrez Gene: ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase 1.
3. Quarona V, Zaccarello G, Chillemi A . CD38 and CD157: a long journey from activation markers to multifunctional molecules . . 84 . 4 . 207–217 . 2013 . 10.1002/cyto.b.21092. 23576305. 205732787 . free . 2318/134656 . free .
4. Lee S, Müller CE . Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and its inhibitors . . 8 . 5 . 823–840 . 2017 . 10.1039/c7md00015d . 6072468 . 30108800.
5. Horenstein AL, Chillemi A, Zaccarello G, Bruzzone S . A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes . Oncoimmunology . 2 . 9 . e26246 . 2013 . 10.4161/onci.26246 . 3850273 . 24319640.
6. Linden J, Koch-Nolte F, Dahl G . Purine Release, Metabolism, and Signaling in the Inflammatory Response . . 37 . 325–347 . 2019 . 10.1146/annurev-immunol-051116-052406 . 30676821. 59250501 .
7. Sek K, Mølck C, Stewart GD, Kats L . Targeting Adenosine Receptor Signaling in Cancer Immunotherapy . . 19 . 12 . 3837 . 2018 . 10.3390/ijms19123837 . 6321150 . 30513816. free .
8. Maddux BA, Goldfine ID . Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit . Diabetes . 49 . 1 . 13–9 . January 2000 . 10615944 . 10.2337/diabetes.49.1.13 . free .