Ectonucleotide pyrophosphatase/phosphodiesterase 1

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (PC-1, CD203a) is an enzyme that in humans is encoded by the ENPP1 gene.[5][6][7]

ENPP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2YS0
Identifiers
Aliases	ENPP1, ARHR2, COLED, M6S1, NPP1, NPPS, PC-1, PCA1, PDNP1, Ectonucleotide pyrophosphatase/phosphodiesterase 1, CD203a
External IDs	OMIM: 173335 MGI: 97370 HomoloGene: 38151 GeneCards: ENPP1
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6q23.2 Start 131,808,016 bp[1] End 131,895,155 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 A4|10 12.26 cM Start 24,637,914 bp[2] End 24,712,159 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleoside-triphosphate diphosphatase activity • calcium ion binding • nucleotide diphosphatase activity • protein homodimerization activity • insulin receptor binding • zinc ion binding • polysaccharide binding • 3'-phosphoadenosine 5'-phosphosulfate binding • metal ion binding • scavenger receptor activity • NADH pyrophosphatase activity • GO:0001948 protein binding • catalytic activity • nucleic acid binding • hydrolase activity • ATP binding • phosphodiesterase I activity • exonuclease activity • cyclic-GMP-AMP hydrolase activity Cellular component • integral component of membrane • membrane • cell membrane • integral component of plasma membrane • extracellular region • cell surface • lysosomal membrane • basolateral plasma membrane • extracellular Biological process • negative regulation of fat cell differentiation • negative regulation of protein autophosphorylation • regulation of bone mineralization • riboflavin metabolic process • biomineral tissue development • nucleoside triphosphate catabolic process • cellular phosphate ion homeostasis • negative regulation of glycogen biosynthetic process • receptor-mediated endocytosis • generation of precursor metabolites and energy • 3'-phosphoadenosine 5'-phosphosulfate metabolic process • negative regulation of glucose import • negative regulation of insulin receptor signaling pathway • negative regulation of cell growth • immune response • cellular response to insulin stimulus • phosphate-containing compound metabolic process • metabolism • inorganic diphosphate transport • sequestering of triglyceride • ATP metabolic process • nucleic acid phosphodiester bond hydrolysis • vesicle-mediated transport • melanocyte differentiation • negative regulation of bone mineralization • negative regulation of hh target transcription factor activity • endocytosis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5167	18605
Ensembl	ENSG00000197594	ENSMUSG00000037370
UniProt	P22413	P06802
RefSeq (mRNA)	NM_006208	NM_008813 NM_001308327 NM_001308329
RefSeq (protein)	NP_006199	NP_001295256 NP_001295258 NP_032839
Location (UCSC)	Chr 6: 131.81 – 131.9 Mb	Chr 10: 24.64 – 24.71 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[8] Another notable nucleotide substrate is nicotinamide adenine dinucleotide (NAD+) which can be hydrolyzed to produce AMP.[8] ADPR can also be hydrolyzed by ENNP1 to produce AMP.[9]

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.[6]

In a tumor microenvironment, AMP generated by ENNP1 can lead to production of adenosine, which suppresses the anti-cancer function of the immune system.[9][10][11]

Interactions

Ectonucleotide pyrophosphatase/phosphodiesterase 1 has been shown to interact with Insulin receptor.[12]

References

1. GRCh38: Ensembl release 89: ENSG00000197594 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000037370 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Funakoshi I, Kato H, Horie K, Yano T, Hori Y, Kobayashi H, Inoue T, Suzuki H, Fukui S, Tsukahara M (June 1992). "Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase". Arch Biochem Biophys. 295 (1): 180–7. doi:10.1016/0003-9861(92)90504-P. PMID 1315502.
6. "Entrez Gene: ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase 1".
7. Quarona V, Zaccarello G, Chillemi A (2013). "CD38 and CD157: a long journey from activation markers to multifunctional molecules". Cytometry Part B. 84 (4): 207–217. doi:10.1002/cyto.b.21092. PMID 23576305.
8. Lee S, Müller CE (2017). "Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and its inhibitors". MedChemComm. 8 (5): 823–840. doi:10.1039/c7md00015d. PMC 6072468. PMID 30108800.
9. Horenstein AL, Chillemi A, Zaccarello G, Bruzzone S (2013). "A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes". ONCOIMMUNOLOGY. 2 (9): e26246. doi:10.4161/onci.26246. PMC 3850273. PMID 24319640.
10. Linden J, Koch-Nolte F, Dahl G (2019). "Purine Release, Metabolism, and Signaling in the Inflammatory Response". ANNUAL REVIEW OF IMMUNOLOGY. 37: 325–347. doi:10.1146/annurev-immunol-051116-052406. PMID 30676821.
11. Sek K, Mølck C, Stewart GD, Kats L (2018). "Targeting Adenosine Receptor Signaling in Cancer Immunotherapy". International Journal of Molecular Sciences. 19 (12): 3837. doi:10.3390/ijms19123837. PMC 6321150. PMID 30513816.
12. Maddux BA, Goldfine ID (January 2000). "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit". Diabetes. 49 (1): 13–9. doi:10.2337/diabetes.49.1.13. PMID 10615944.

Further reading

• Abate N, Chandalia M, Di Paola R, Foster DW, Grundy SM, Trischitta V (2007). "Mechanisms of disease: Ectonucleotide pyrophosphatase phosphodiesterase 1 as a 'gatekeeper' of insulin receptors". Nature Clinical Practice Endocrinology & Metabolism. 2 (12): 694–701. doi:10.1038/ncpendmet0367. PMID 17143316.
• Bacci S, De Cosmo S, Prudente S, Trischitta V (2007). "ENPP1 gene, insulin resistance and related clinical outcomes". Current Opinion in Clinical Nutrition and Metabolic Care. 10 (4): 403–9. doi:10.1097/MCO.0b013e3281e386c9. PMID 17563456.
• Fadini GP, Pauletto P, Avogaro A, Rattazzi M (2007). "The good and the bad in the link between insulin resistance and vascular calcification". Atherosclerosis. 193 (2): 241–4. doi:10.1016/j.atherosclerosis.2007.05.015. PMID 17606264.
• Buckley MF, Loveland KA, McKinstry WJ, Garson OM, Goding JW (1990). "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. PMID 2211644.
• Belli SI, Mercuri FA, Sali A, Goding JW (1995). "Autophosphorylation of PC-1 (alkaline phosphodiesterase I/nucleotide pyrophosphatase) and analysis of the active site". Eur. J. Biochem. 228 (3): 669–76. doi:10.1111/j.1432-1033.1995.tb20308.x. PMID 7737162.
• Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, Spencer S, Grupe A, Henzel W, Stewart TA (1995). "Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus". Nature. 373 (6513): 448–51. doi:10.1038/373448a0. PMID 7830796.
• Belli SI, Goding JW (1995). "Biochemical characterization of human PC-1, an enzyme possessing alkaline phosphodiesterase I and nucleotide pyrophosphatase activities". Eur. J. Biochem. 226 (2): 433–43. doi:10.1111/j.1432-1033.1994.tb20068.x. PMID 8001561.
• Huang R, Rosenbach M, Vaughn R, Provvedini D, Rebbe N, Hickman S, Goding J, Terkeltaub R (1994). "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. doi:10.1172/JCI117370. PMC 296131. PMID 8040311.
• Jin-Hua P, Goding JW, Nakamura H, Sano K (1998). "Molecular cloning and chromosomal localization of PD-Ibeta (PDNP3), a new member of the human phosphodiesterase I genes". Genomics. 45 (2): 412–5. doi:10.1006/geno.1997.4949. PMID 9344668.
• 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 (1999). "Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)". Hum. Genet. 104 (6): 492–7. doi:10.1007/s004390050993. PMID 10453738.
• Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, Ercolino T, Scarlato G, Iacoviello L, Vigneri R, Tassi V, Trischitta V (1999). "A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance". Diabetes. 48 (9): 1881–4. doi:10.2337/diabetes.48.9.1881. PMID 10480624.
• Andoh K, Piao JH, Terashima K, Nakamura H, Sano K (1999). "Genomic structure and promoter analysis of the ecto-phosphodiesterase I gene (PDNP3) expressed in glial cells". Biochim. Biophys. Acta. 1446 (3): 213–24. doi:10.1016/s0167-4781(99)00090-1. PMID 10524196.
• Maddux BA, Goldfine ID (2000). "Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit". Diabetes. 49 (1): 13–9. doi:10.2337/diabetes.49.1.13. PMID 10615944.
• Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, Kalhoff H, Sano K, Boisvert WA, Superti-Furga A, Terkeltaub R (2001). "PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification". Am. J. Pathol. 158 (2): 543–54. doi:10.1016/S0002-9440(10)63996-X. PMC 1850320. PMID 11159191.
• Frittitta L, Baratta R, Spampinato D, Di Paola R, Pizzuti A, Vigneri R, Trischitta V (2001). "The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance". J. Clin. Endocrinol. Metab. 86 (12): 5888–91. doi:10.1210/jc.86.12.5888. PMID 11739459.
• Koshizuka Y, Kawaguchi H, Ogata N, Ikeda T, Mabuchi A, Seichi A, Nakamura Y, Nakamura K, Ikegawa S (2002). "Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine". J. Bone Miner. Res. 17 (1): 138–44. doi:10.1359/jbmr.2002.17.1.138. PMID 11771660.
• de Azevedo MJ, Dalmáz CA, Caramori ML, Pecis M, Esteves JF, Maia AL, Gross JL (2003). "ACE and PC-1 gene polymorphisms in normoalbuminuric Type 1 diabetic patients: a 10-year prospective study". J. Diabetes Complicat. 16 (4): 255–62. doi:10.1016/s1056-8727(01)00185-4. PMID 12126783.
• 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 (2003). "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. doi:10.1093/ndt/17.8.1402. PMID 12147786.
• Jacobsen P, Grarup N, Tarnow L, Parving HH, Pedersen O (2003). "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. doi:10.1093/ndt/17.8.1408. PMID 12147787.