N-Acetylglucosamine-1-Phosphate Transferase, Alpha/Beta and Gamma Subunits (GNPTAB, GNPTG)

Reference work entry


GlcNAc-1-phosphotransferase catalyzes the transfer of a GlcNAc-1-phosphate residue from UDP-GlcNAc to C6 positions of selected mannoses in high-mannose-type oligosaccharides of the hydrolases (Goldberg and Kornfeld 1981; Natowicz et al. 1982; Varki and Kornfeld 1983). At a biological level this reaction is followed by the removal of the terminal GlcNAc by an N-acetylglucosamine-1-phosphodiester α-N-acetyl-glucosaminidase, usually referred to as “uncovering enzyme” (UCE;  see Chap. 78, “Hyaluronan Synthase 1-3 (HAS1-3)”; Article ID: 332135). Sequential action of these two enzymes results in the formation of the mannose-6-phosphate (Man-6-P) marker, a specific tag acquired by lysosomal hydrolases that ensures recognition by M6P receptors and delivery to the endosomal/lysosomal system (Braulke and Bonifacino 2009).


Lysosomal Enzyme Retinal Degeneration Lysosomal Storage Disorder Acid Hydrolase Lysosomal Hydrolase 


  1. Bao M, Booth JL, Elmendorf BJ, Canfield WM (1996a) Bovine UDP-N-acetylglucosamine: lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase I. Purification and subunit structure. J Biol Chem 271:31437–31445PubMedCrossRefGoogle Scholar
  2. Bao M, Elmendorf BJ, Booth JL, Drake RR, Canfield WM (1996b) Bovine UDP-N-acetylglucosamine: lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase II. Enzymatic characterization and identification of the catalytic subunit. J Biol Chem 271:31446–31451PubMedCrossRefGoogle Scholar
  3. Baranski TJ, Faust PL, Kornfeld S (1990) Generation of a lysosomal enzyme targeting signal in the secretory protein pepsinogen. Cell 63:281–291PubMedCrossRefGoogle Scholar
  4. Baranski TJ, Koelsch G, Hartsuck JA, Kornfeld S (1991) Mapping and molecular modeling of a recognition domain for lysosomal enzyme targeting. J Biol Chem 266:23365–23372PubMedGoogle Scholar
  5. Bargal R, Zeigler M, Abu-Libdeh B, Zuri V, Mandel H, Ben Neriah Z, Stewart F, Elcioglu N, Hindi T, Le Merrer M, Bach G, Raas-Rothschild A (2006) When mucolipidosis III meets mucolipidosis II: GNPTA gene mutations in 24 patients. Mol Genet Metab 88:359–363, Erratum in: Mol Genet Metab. 2007; 91:299PubMedCrossRefGoogle Scholar
  6. Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793:605–614. doi:10.1016/j.bbamcr.2008.10.016PubMedCrossRefGoogle Scholar
  7. Cantor AB, Baranski TJ, Kornfeld S (1992) Lysosomal enzyme phosphorylation II. Protein recognition determinants in either lobe of procathepsin D are sufficient for phosphorylation of both the amino and carboxyl lobe oligosaccharides. J Biol Chem 267:23349–23356PubMedGoogle Scholar
  8. Cathey SS, Kudo M, Tiede S, Raas-Rothschild A, Braulke T, Beck M, Taylor HA, Canfield WM, Leroy JG, Neufeld EF, McKusick VA (2008) Molecular order in mucolipidosis II and III nomenclature. Am J Med Genet A 146A:512–513. doi:10.1002/ajmg.a.32193PubMedCrossRefGoogle Scholar
  9. Coutinho MF, da Silva SL, Lacerda L, Quental S, Wibrand F, Lund AM, Johansen KB, Prata MJ, Alves S (2011a) Alu-Alu recombination underlying the first large genomic deletion in GlcNAc-phosphotransferase alpha/beta (GNPTAB) gene in a MLII alpha/beta patient. JIMD Rep 4:117–124. doi:10.1007/8904_2011_83PubMedCentralPubMedCrossRefGoogle Scholar
  10. Coutinho MF, Encarnação M, Gomes R, da Silva Santos L, Martins S, Sirois-Gagnon D, Bargal R, Filocamo M, Raas-Rothschild A, Tappino B, Laprise C, Cury GK, Schwartz IV, Artigalás O, Prata MJ, Alves S (2011b) Origin and spread of a common deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity. Clin Genet 80:273–280. doi:10.1111/j.1399-0004.2010.01539.xPubMedCrossRefGoogle Scholar
  11. Coutinho MF, Prata MJ, Alves S (2012) Mannose-6-phosphate pathway: a review on its role in lysosomal function and dysfunction. Mol Genet Metab 105:542–550. doi:10.1016/j.ymgme.2011.12.012PubMedCrossRefGoogle Scholar
  12. Encarnação M, Lacerda L, Costa R, Prata MJ, Coutinho MF, Ribeiro H, Lopes L, Pineda M, Ignatius J, Galvez H, Mustonen A, Vieira P, Lima MR, Alves S (2009) Molecular analysis of the GNPTAB and GNPTG genes in 13 patients with mucolipidosis type II or type III – identification of eight novel mutations. Clin Genet 76:76–84. doi:10.1111/j.1399-0004.2009.01185.xPubMedCrossRefGoogle Scholar
  13. Encarnação M, Kollmann K, Trusch M, Braulke T, Pohl S (2010) Post-translational modifications of the gamma-subunit affect intracellular trafficking and complex assembly of GlcNAc-1-phosphotransferase. J Biol Chem 286:5311–5318. doi:10.1074/jbc.M110.202382PubMedCrossRefGoogle Scholar
  14. Franke M, Braulke T, Storch S (2013) Transport of the GlcNAc-1-phosphotransferase α/β-subunit precursor protein to the Golgi apparatus requires a combinatorial sorting motif. J Biol Chem 288:1238–1249. doi:10.1074/jbc.M112.407676PubMedCrossRefGoogle Scholar
  15. Gelfman CM, Vogel P, Issa TM, Turner CA, Lee WS, Kornfeld S, Rice DS (2007) Mice lacking alpha/beta subunits of GlcNAc-1-phosphotransferase exhibit growth retardation, retinal degeneration, and secretory cell lesions. Invest Ophthalmol Vis Sci 48:5221–5228PubMedCrossRefGoogle Scholar
  16. Goldberg DE, Kornfeld S (1981) The phosphorylation of beta-glucuronidase oligosaccharides in mouse P388D1 cells. J Biol Chem 256:13060–13067PubMedGoogle Scholar
  17. Hasilik A, Waheed A, von Figura K (1981) Enzymatic phosphorylation of lysosomal enzymes in the presence of UDP-N-acetylglucosamine. Absence of the activity in I-cell fibroblasts. Biochem Biophys Res Commun 98:761–767PubMedCrossRefGoogle Scholar
  18. Kang C, Riazuddin S, Mundorff J, Krasnewich D, Friedman P, Mullikin JC, Drayna D (2010) Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. N Engl J Med 362:677–685. doi:10.1056/NEJMoa0902630PubMedCentralPubMedCrossRefGoogle Scholar
  19. Ketcham CM, Kornfeld S (1992) Characterization of UDP-N-acetylglucosamine:glycoprotein N-acetylglucosamine-1-phosphotransferase from Acanthamoeba castellanii. J Biol Chem 267:11654–11659PubMedGoogle Scholar
  20. Kollmann K, Pohl S, Marschner K, Encarnação M, Sakwa I, Tiede S, Poorthuis BJ, Lübke T, Müller-Loennies S, Storch S, Braulke T (2010) Mannose phosphorylation in health and disease. Eur J Cell Biol 89:117–123. doi:10.1016/j.ejcb.2009.10.008PubMedCrossRefGoogle Scholar
  21. Kollmann K, Damme M, Markmann S, Morelle W, Schweizer M, Hermans-Borgmeyer I, Röchert AK, Pohl S, Lübke T, Michalski JC, Käkelä R, Walkley SU, Braulke T (2012) Lysosomal dysfunction causes neurodegeneration in mucolipidosis II ‘knock-in’ mice. Brain 135:2661–2675. doi:10.1093/brain/aws209PubMedCrossRefGoogle Scholar
  22. Kornfeld S, Sly WS (2001) I-cell disease and pseudo-Hurler polydystrophy: disorders of lysosomal enzyme phosphorylation and localization. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. MacGraw-Hill, New York, pp 3421–3452Google Scholar
  23. Kudo M, Bao M, D’Souza A, Ying F, Pan H, Roe BA, Canfield WM (2005) The alpha- and beta-subunits of the human UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase [corrected] are encoded by a single cDNA. J Biol Chem 280:36141–36149PubMedCrossRefGoogle Scholar
  24. Kudo M, Brem MS, Canfield WM (2006) Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha/beta -subunits precursor gene. Am J Hum Genet 78:451–463PubMedCentralPubMedCrossRefGoogle Scholar
  25. Lang L, Kornfeld S (1984) A simplified procedure for synthesizing large quantities of highly purified uridine [beta-32P]diphospho-N-acetylglucosamine. Anal Biochem 140:264–269PubMedCrossRefGoogle Scholar
  26. Lang L, Reitman M, Tang J, Roberts RM, Kornfeld S (1984) Lysosomal enzyme phosphorylation. Recognition of a protein-dependent determinant allows specific phosphorylation of oligosaccharides present on lysosomal enzymes. J Biol Chem 259:14663–14671PubMedGoogle Scholar
  27. Lee WS, Payne BJ, Gelfman CM, Vogel P, Kornfeld S (2007) Murine UDP-GlcNAc: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase lacking the gamma-subunit retains substantial activity toward acid hydrolases. J Biol Chem 282:27198–27203PubMedCrossRefGoogle Scholar
  28. Leroy JG, Spranger JW (1970) I-cell disease. N Engl J Med 283:598–599PubMedGoogle Scholar
  29. Marschner K, Kollmann K, Schweizer M, Braulke T, Pohl S (2011) A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism. Science 333:87–90. doi:10.1126/science.1205677PubMedCrossRefGoogle Scholar
  30. Natowicz M, Baenziger JU, Sly WS (1982) Structural studies of the phosphorylated high mannose-type oligosaccharides on human beta-glucuronidase. J Biol Chem 257:4412–4420PubMedGoogle Scholar
  31. Nishikawa A, Gregory W, Frenz J, Cacia J, Kornfeld S (1997) The phosphorylation of bovine DNase I Asn-linked oligosaccharides is dependent on specific lysine and arginine residues. J Biol Chem 272:19408–19412PubMedCrossRefGoogle Scholar
  32. Otomo T, Muramatsu T, Yorifuji T, Okuyama T, Nakabayashi H, Fukao T, Ohura T, Yoshino M, Tanaka A, Okamoto N, Inui K, Ozono K, Sakai N (2009) Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype-phenotype correlation. J Hum Genet 54:145–151. doi:10.1038/jhg.2009.3PubMedCrossRefGoogle Scholar
  33. Pohl S, Tiede S, Castrichini M, Cantz M, Gieselmann V, Braulke T (2009) Compensatory expression of human N-acetylglucosaminyl-1-phosphotransferase subunits in mucolipidosis type III gamma. Biochim Biophys Acta 1792:221–225. doi:10.1016/j.bbadis.2009.01.009PubMedCrossRefGoogle Scholar
  34. Pohl S, Encarnacão M, Castrichini M, Müller-Loennies S, Muschol N, Braulke T (2010) Loss of N-acetylglucosamine-1-phosphotransferase gamma subunit due to intronic mutation in GNPTG causes mucolipidosis type III gamma: Implications for molecular and cellular diagnostics. Am J Med Genet A 152A:124–132. doi:10.1002/ajmg.a.33170PubMedCrossRefGoogle Scholar
  35. Qian Y, Lee I, Lee WS, Qian M, Kudo M, Canfield WM, Lobel P, Kornfeld S (2010) Functions of the alpha, beta, and gamma subunits of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. J Biol Chem 285:3360–3370. doi:10.1074/jbc.M109.068650PubMedCrossRefGoogle Scholar
  36. Raas-Rothschild A, Cormier-Daire V, Bao M, Genin E, Salomon R, Brewer K, Zeigler M, Mandel H, Toth S, Roe B, Munnich A, Canfield WM (2000) Molecular basis of variant pseudo-hurler polydystrophy (mucolipidosis IIIC). J Clin Invest 105:673–681PubMedCentralPubMedCrossRefGoogle Scholar
  37. Reitman ML, Kornfeld S (1981a) UDP-N-acetylglucosamine: glycoprotein N-acetylglucosamine-1-phosphotransferase. Proposed enzyme for the phosphorylation of the high mannose oligosaccharide units of lysosomal enzymes. J Biol Chem 256:4275–4281PubMedGoogle Scholar
  38. Reitman ML, Kornfeld S (1981b) Lysosomal enzyme targeting. N-Acetylglucosaminylphosphotransferase selectively phosphorylates native lysosomal enzymes. J Biol Chem 256:11977–11980PubMedGoogle Scholar
  39. Reitman ML, Lang L, Kornfeld S (1984) UDP-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. Methods Enzymol 107:163–172PubMedCrossRefGoogle Scholar
  40. Sommerlade HJ, Selmer T, Ingendoh A, Gieselmann V, von Figura K, Neifer K, Schmidt B (1994) Glycosylation and phosphorylation of arylsulfatase A. J Biol Chem 269:20977–20981PubMedGoogle Scholar
  41. Spranger JW, Wiedemann HR (1970) The genetic mucolipidoses. Diagnosis and differential diagnosis. Humangenetik 9:113–139PubMedGoogle Scholar
  42. Tappino B, Regis S, Corsolini F, Filocamo M (2008) An Alu insertion in compound heterozygosity with a microduplication in GNPTAB gene underlies Mucolipidosis II. Mol Genet Metab 93:129–133PubMedCrossRefGoogle Scholar
  43. Tappino B, Chuzhanova NA, Regis S, Dardis A, Corsolini F, Stroppiano M, Tonoli E, Beccari T, Rosano C, Mucha J, Blanco M, Szlago M, Di Rocco M, Cooper DN, Filocamo M (2009) Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase alpha- and beta-subunit (GNPTAB) gene mutations causing mucolipidosis types II alpha/beta and III alpha/beta in 46 patients. Hum Mutat 30:E956–E973. doi:10.1002/humu.21099PubMedCrossRefGoogle Scholar
  44. Tiede S, Storch S, Lübke T, Henrissat B, Bargal R, Raas-Rothschild A, Braulke T (2005) Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. Nat Med 11:1109–1112PubMedCrossRefGoogle Scholar
  45. Umehara F, Matsumoto W, Kuriyama M, Sukegawa K, Gasa S, Osame M (1997) Mucolipidosis III (pseudo-Hurler polydystrophy); clinical studies in aged patients in one family. J Neurol Sci 146:167–172PubMedCrossRefGoogle Scholar
  46. Varki A, Kornfeld S (1983) The spectrum of anionic oligosaccharides released by endo-beta-N-acetylglucosaminidase H from glycoproteins Structural studies and interactions with the phosphomannosyl receptor. J Biol Chem 258:2808–2818PubMedGoogle Scholar
  47. Vogel P, Payne BJ, Read R, Lee WS, Gelfman CM, Kornfeld S (2009) Comparative pathology of murine mucolipidosis types II and IIIC. Vet Pathol 46:313–324. doi:10.1354/vp.46-2-313PubMedCentralPubMedCrossRefGoogle Scholar
  48. Waheed A, Hasilik A, von Figura K (1982) UDP-N-acetylglucosamine: lysosomal enzyme precursor N-acetylglucosamine-1-phosphotransferase Partial purification and characterization of the rat liver Golgi enzyme. J Biol Chem 257:12322–12331PubMedGoogle Scholar
  49. Waheed A, Pohlmann R, Hasilik A, von Figura K (1981) Subcellular location of two enzymes involved in the synthesis of phosphorylated recognition markers in lysosomal enzymes. J Biol Chem 256:4150–4152PubMedGoogle Scholar
  50. Zhao KW, Yeh R, Miller AL (1992) Purification and characterization of human lymphoblast N-acetylglucosamine-1-phosphotransferase. Glycobiology 2:119–125PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Department of Human GeneticsNational Health Institute Doutor Ricardo Jorge, IPPortoPortugal

Personalised recommendations