Ectonucleotide pyrophosphatase/phosphodiesterase 1

ENPP1
Identifiers
Aliases	ENPP1, ARHR2, COLED, M6S1, NPP1, NPPS, PC-1, PCA1, PDNP1, Ectonucleotide pyrophosphatase/phosphodiesterase 1, CD203a
External IDs	OMIM: 173335; MGI: 97370; GeneCards: ENPP1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2YS0
Enzyme activity
Gene location (Human)
Chr.	Chromosome 6 (human)
End	131,895,155 bp
Gene location (Mouse)
Chr.	Chromosome 10 (mouse)
End	24,588,057 bp
RNA expression pattern
	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
	; ;
	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
Databases	NCBI: entry; OMA: entry
	5167
	18605
	ENSG00000197594
	ENSMUSG00000037370
	P22413
	P06802
	NM_006208
	NM_008813; NM_001308327; NM_001308329
	NP_006199
	NP_001295256; NP_001295258; NP_032839
	Wikidata
View/Edit Human	View/Edit Mouse

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

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

The main substrate of ENPP1 is adenosine triphosphate (ATP), which is cleaved into adenosine monophosphate (AMP) and diphosphate. Other notable substrates include cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), nicotinamide adenine dinucleotide (NAD+) and cADPR.

ENPP3, a paralog of ENPP1, has also been identified as a major extracellular cGAMP hydrolase and is the second metazoan enzyme known to perform this function.

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 ENPP1 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.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000197594 – Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000037370 – Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ Funakoshi I, Kato H, Horie K, Yano T, Hori Y, Kobayashi H, et al. (June 1992). "Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase". Archives of Biochemistry and Biophysics. 295 (1): 180–187. doi:10.1016/0003-9861(92)90504-P. PMID 1315502.
1 2 "Entrez Gene: ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase 1".
↑ Quarona V, Zaccarello G, Chillemi A (2013). "CD38 and CD157: a long journey from activation markers to multifunctional molecules". Cytometry. Part B, Clinical Cytometry. 84 (4): 207–217. doi:10.1002/cyto.b.21092. hdl:2318/134656. PMID 23576305. S2CID 205732787.
1 2 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.
↑ Li L, Yin Q, Kuss P, Maliga Z, Millán JL, Wu H, et al. (December 2014). "Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs". Nature Chemical Biology. 10 (12): 1043–1048. doi:10.1038/nchembio.1661. PMC 4232468. PMID 25344812.
1 2 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.
↑ Mardjuki R, Wang S, Carozza J, Zirak B, Subramanyam V, Abhiraman G, et al. (May 2024). "Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint". Cell Reports. 43 (5) 114209. doi:10.1016/j.celrep.2024.114209. PMC 13268100. PMID 38749434.
↑ 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. S2CID 59250501.
↑ 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.
↑ 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): 13–19. doi:10.2337/diabetes.49.1.13. PMID 10615944.

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): 403–409. 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): 241–244. 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". The Journal of Biological Chemistry. 265 (29): 17506–17511. 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". European Journal of Biochemistry. 228 (3): 669–676. doi:10.1111/j.1432-1033.1995.tb20308.x. PMID 7737162.
Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, et al. (1995). "Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus". Nature. 373 (6513): 448–451. 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". European Journal of Biochemistry. 226 (2): 433–443. doi:10.1111/j.1432-1033.1994.tb20068.x. PMID 8001561.
Huang R, Rosenbach M, Vaughn R, Provvedini D, Rebbe N, Hickman S, et al. (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". The Journal of Clinical Investigation. 94 (2): 560–567. 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): 412–415. doi:10.1006/geno.1997.4949. PMID 9344668.
Nakamura I, Ikegawa S, Okawa A, Okuda S, Koshizuka Y, Kawaguchi H, et al. (1999). "Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)". Human Genetics. 104 (6): 492–497. doi:10.1007/s004390050993. PMID 10453738. S2CID 238056.
Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, et al. (1999). "A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance". Diabetes. 48 (9): 1881–1884. 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". Biochimica et Biophysica Acta. 1446 (3): 213–224. doi:10.1016/s0167-4781(99)00090-1. PMID 10524196.
Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, et al. (2001). "PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification". The American Journal of Pathology. 158 (2): 543–554. 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, et al. (2001). "The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance". The Journal of Clinical Endocrinology and Metabolism. 86 (12): 5888–5891. doi:10.1210/jcem.86.12.8108. PMID 11739459.
Koshizuka Y, Kawaguchi H, Ogata N, Ikeda T, Mabuchi A, Seichi A, et al. (2002). "Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine". Journal of Bone and Mineral Research. 17 (1): 138–144. 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, et al. (2003). "ACE and PC-1 gene polymorphisms in normoalbuminuric Type 1 diabetic patients: a 10-year prospective study". Journal of Diabetes and Its Complications. 16 (4): 255–262. doi:10.1016/s1056-8727(01)00185-4. PMID 12126783.
De Cosmo S, Miscio G, Zucaro L, Margaglione M, Argiolas A, Thomas S, et al. (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". Nephrology, Dialysis, Transplantation. 17 (8): 1402–1407. 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". Nephrology, Dialysis, Transplantation. 17 (8): 1408–1412. doi:10.1093/ndt/17.8.1408. PMID 12147787.

This article on a gene on human chromosome 6 is a stub. You can help Wikipedia by adding missing information.

[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000197594 – Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 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.

[Funakoshi_1992-5] Funakoshi I, Kato H, Horie K, Yano T, Hori Y, Kobayashi H, et al. (June 1992). "Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase". Archives of Biochemistry and Biophysics. 295 (1): 180–187. doi:10.1016/0003-9861(92)90504-P. PMID 1315502.

[entrez-6] 1 2 "Entrez Gene: ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase 1".

[Quarona_2013-7] Quarona V, Zaccarello G, Chillemi A (2013). "CD38 and CD157: a long journey from activation markers to multifunctional molecules". Cytometry. Part B, Clinical Cytometry. 84 (4): 207–217. doi:10.1002/cyto.b.21092. hdl:2318/134656. PMID 23576305. S2CID 205732787.

[Lee_2017-8] 1 2 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] Li L, Yin Q, Kuss P, Maliga Z, Millán JL, Wu H, et al. (December 2014). "Hydrolysis of 2'3'-cGAMP by ENPP1 and design of nonhydrolyzable analogs". Nature Chemical Biology. 10 (12): 1043–1048. doi:10.1038/nchembio.1661. PMC 4232468. PMID 25344812.

[Horenstein_2013-10] 1 2 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.

[11] Mardjuki R, Wang S, Carozza J, Zirak B, Subramanyam V, Abhiraman G, et al. (May 2024). "Identification of the extracellular membrane protein ENPP3 as a major cGAMP hydrolase and innate immune checkpoint". Cell Reports. 43 (5) 114209. doi:10.1016/j.celrep.2024.114209. PMC 13268100. PMID 38749434.

[Linden_2019-12] 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. S2CID 59250501.

[Sek_2018-13] 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.

[Maddux_2000-14] 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): 13–19. doi:10.2337/diabetes.49.1.13. PMID 10615944.