Skip to main content

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

  • Reference work entry
  • First Online:
  • 321 Accesses

Abstract

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).

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   799.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • 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 271:31437–31445

    Article  CAS  PubMed  Google Scholar 

  • 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 271:31446–31451

    Article  CAS  PubMed  Google Scholar 

  • Baranski TJ, Faust PL, Kornfeld S (1990) Generation of a lysosomal enzyme targeting signal in the secretory protein pepsinogen. Cell 63:281–291

    Article  CAS  PubMed  Google Scholar 

  • Baranski TJ, Koelsch G, Hartsuck JA, Kornfeld S (1991) Mapping and molecular modeling of a recognition domain for lysosomal enzyme targeting. J Biol Chem 266:23365–23372

    CAS  PubMed  Google Scholar 

  • 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; 91:299

    Article  CAS  PubMed  Google Scholar 

  • Braulke T, Bonifacino JS (2009) Sorting of lysosomal proteins. Biochim Biophys Acta 1793:605–614. doi:10.1016/j.bbamcr.2008.10.016

    Article  CAS  PubMed  Google Scholar 

  • 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 267:23349–23356

    CAS  PubMed  Google Scholar 

  • 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.32193

    Article  PubMed  Google Scholar 

  • 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_83

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.x

    Article  CAS  PubMed  Google Scholar 

  • 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.2011.12.012

    Article  CAS  PubMed  Google Scholar 

  • 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.x

    Article  PubMed  Google Scholar 

  • 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.M110.202382

    Article  PubMed  Google Scholar 

  • 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.M112.407676

    Article  CAS  PubMed  Google Scholar 

  • 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 48:5221–5228

    Article  PubMed  Google Scholar 

  • Goldberg DE, Kornfeld S (1981) The phosphorylation of beta-glucuronidase oligosaccharides in mouse P388D1 cells. J Biol Chem 256:13060–13067

    CAS  PubMed  Google Scholar 

  • 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 98:761–767

    Article  CAS  PubMed  Google Scholar 

  • 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/NEJMoa0902630

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ketcham CM, Kornfeld S (1992) Characterization of UDP-N-acetylglucosamine:glycoprotein N-acetylglucosamine-1-phosphotransferase from Acanthamoeba castellanii. J Biol Chem 267:11654–11659

    CAS  PubMed  Google Scholar 

  • 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.2009.10.008

    Article  CAS  PubMed  Google Scholar 

  • 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/aws209

    Article  CAS  PubMed  Google Scholar 

  • 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 3421–3452

    Google Scholar 

  • 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 280:36141–36149

    Article  CAS  PubMed  Google Scholar 

  • 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 78:451–463

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lang L, Kornfeld S (1984) A simplified procedure for synthesizing large quantities of highly purified uridine [beta-32P]diphospho-N-acetylglucosamine. Anal Biochem 140:264–269

    Article  CAS  PubMed  Google Scholar 

  • 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 259:14663–14671

    CAS  PubMed  Google Scholar 

  • 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 282:27198–27203

    Article  CAS  PubMed  Google Scholar 

  • Leroy JG, Spranger JW (1970) I-cell disease. N Engl J Med 283:598–599

    CAS  PubMed  Google Scholar 

  • 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.1205677

    Article  CAS  PubMed  Google Scholar 

  • Natowicz M, Baenziger JU, Sly WS (1982) Structural studies of the phosphorylated high mannose-type oligosaccharides on human beta-glucuronidase. J Biol Chem 257:4412–4420

    CAS  PubMed  Google Scholar 

  • 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 272:19408–19412

    Article  CAS  PubMed  Google Scholar 

  • 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.2009.3

    Article  CAS  PubMed  Google Scholar 

  • 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.2009.01.009

    Article  CAS  PubMed  Google Scholar 

  • 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.33170

    Article  CAS  PubMed  Google Scholar 

  • 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.M109.068650

    Article  CAS  PubMed  Google Scholar 

  • 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 105:673–681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 256:4275–4281

    CAS  PubMed  Google Scholar 

  • Reitman ML, Kornfeld S (1981b) Lysosomal enzyme targeting. N-Acetylglucosaminylphosphotransferase selectively phosphorylates native lysosomal enzymes. J Biol Chem 256:11977–11980

    CAS  PubMed  Google Scholar 

  • Reitman ML, Lang L, Kornfeld S (1984) UDP-N-acetylglucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. Methods Enzymol 107:163–172

    Article  CAS  PubMed  Google Scholar 

  • 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 269:20977–20981

    CAS  PubMed  Google Scholar 

  • Spranger JW, Wiedemann HR (1970) The genetic mucolipidoses. Diagnosis and differential diagnosis. Humangenetik 9:113–139

    CAS  PubMed  Google Scholar 

  • 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 93:129–133

    Article  CAS  PubMed  Google Scholar 

  • 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.21099

    Article  PubMed  Google Scholar 

  • 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 11:1109–1112

    Article  CAS  PubMed  Google Scholar 

  • 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 146:167–172

    Article  CAS  PubMed  Google Scholar 

  • 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 258:2808–2818

    CAS  PubMed  Google Scholar 

  • 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.46-2-313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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 257:12322–12331

    CAS  PubMed  Google Scholar 

  • 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 256:4150–4152

    CAS  PubMed  Google Scholar 

  • Zhao KW, Yeh R, Miller AL (1992) Purification and characterization of human lymphoblast N-acetylglucosamine-1-phosphotransferase. Glycobiology 2:119–125

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maria Francisca Coutinho .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Japan

About this entry

Cite this entry

Coutinho, M.F. (2014). N-Acetylglucosamine-1-Phosphate Transferase, Alpha/Beta and Gamma Subunits (GNPTAB, GNPTG). In: Taniguchi, N., Honke, K., Fukuda, M., Narimatsu, H., Yamaguchi, Y., Angata, T. (eds) Handbook of Glycosyltransferases and Related Genes. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54240-7_101

Download citation

Publish with us

Policies and ethics