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.

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; OMA:ENPP1 - orthologs
Gene location (Human) Chr. Chromosome 6 (human) Band 6q23.2 Start 131,808,016 bp End 131,895,155 bp
Gene location (Mouse) Chr. Chromosome 10 (mouse) Band 10 A4|10 12.26 cM Start 24,513,812 bp End 24,588,057 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia decidua cartilage tissue tail of epididymis Achilles tendon tendon of biceps brachii liver right lobe of liver synovial joint corpus epididymis Top expressed in epithelium of lens fossa condyle transitional epithelium of urinary bladder body of femur right kidney ankle umbilical cord ascending aorta aortic valve More reference expression data BioGPS 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 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 plasma membrane integral component of plasma membrane extracellular region cell surface lysosomal membrane basolateral plasma membrane extracellular space 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: 24.51 – 24.59 Mb PubMed search
Wikidata
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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. 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.

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.

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

Interactions

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

See also

• Nucleotide pyrophosphatase/phosphodiesterase

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. S2CID 8907895.
• 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. S2CID 13172655.
• 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. doi:10.1016/S0021-9258(18)38193-6. 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. Bibcode:1995Natur.373..448M. doi:10.1038/373448a0. PMID 7830796. S2CID 4359358.
• 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. S2CID 238056.
• 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/jcem.86.12.8108. 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. S2CID 20481601.
• 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.