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Gene Review

GM2A  -  GM2 ganglioside activator

Homo sapiens

Synonyms: Cerebroside sulfate activator protein, GM2-AP, Ganglioside GM2 activator, SAP-3, Sphingolipid activator protein 3
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Disease relevance of GM2A


High impact information on GM2A

  • Our results showed that both the truncated sortilin and the sortilin siRNA block the traffic of GM2AP and prosaposin to the lysosomal compartment [6].
  • Furthermore, a dominant-negative mutant GGA prevented the trafficking of prosaposin and GM2AP to lysosomes [6].
  • Although the cultured fibroblasts of both patients produce normal levels of activator mRNA, they lack a lysosomal form of GM2AP [7].
  • The presence of GM2A mRNA in human tissues and the selective stimulation of NeuAc hydrolysis by GM2A protein indicate that this activator protein may be involved in the catabolism of GM2 through the asialo-GM2 pathway [3].
  • GM2A mRNA is an RNA alternative splicing product that contains exons 1, 2, 3, and intron 3 of the genomic DNA sequence of GM2 activator protein (Klima, H., Tanaka, A., Schnabel, D., Nakano, T., Schröder, M., Suzuki, K., and Sandhoff, K. (1991) FEBS Lett. 289, 260-264) [3].

Chemical compound and disease context of GM2A


Biological context of GM2A


Anatomical context of GM2A

  • SAP1 and SAP3 transcripts were first detected 42 h after inoculation of RHE, while at the same time, slight morphological alterations in the epithelium were documented by light microscopy [12].
  • It has been postulated that GM2-AP extracts single GM2 molecules from membranes and presents them in soluble form to beta-hexosaminidase A for cleavage of N-acetyl-d-galactosamine and conversion to GM3 [13].
  • GM2 activator protein (GM2AP) is a specific protein cofactor that stimulates the enzymatic hydrolysis of the GalNAc from GM2, a sialic acid containing glycosphingolipid, both in vitro and in lysosomes [5].
  • Sap1 to Sap3 antigens were found on yeast and hyphal cells, while Sap4 to Sap6 antigens were predominantly found on hyphal cells in close contact with host cells, in particular, eosinophilic leukocytes [14].
  • GM2-activator protein (GM2-AP) is a lipid transfer protein that has the ability to stimulate the enzymatic processing of gangliosides as well as T-cell activation through lipid presentation [15].

Associations of GM2A with chemical compounds

  • The high affinity of GM2-AP for GM2 is based on specfic recognition of the oligosaccharide moiety as well as the ceramide lipid tail [13].
  • High ammonium sulfate concentration (1.6 M or 21.1%) masks this inhibitory effect, possibly due to the alteration of the ionic property of GM2AP [5].
  • Several recent reports suggest that GM2AP might have functions other than stimulating the conversion of GM2 into GM3 by beta-hexosaminidase A, such as inhibiting the activity of platelet activating factor and enhancing the degradation of phosphatidylcholine by phospholipase D (PLD) [5].
  • However, recent studies on the intracellular trafficking of the non-enzymic lysosomal proteins prosaposin and GM2 activator (GM2AP) demonstrated that they use an alternative receptor termed "sortilin". Existing evidence suggests that some hydrolases traffic to the lysosomes in a mannose 6-phophate-indepentend manner [16].
  • These results suggest that GM2AP assumed a more organized alpha-helical conformation with the tryptophan residues moving from the polar medium toward the hydrophobic environment of the protein [17].

Other interactions of GM2A

  • The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A gene loci [1].
  • Sap1, Sap2 and Sap3 isoenzymes were found to be related to the vaginopathic potential of C. albicans; Sap4, Sap5 and Sap6 isoenzymes were found to be correlated with systemic infections [18].
  • The attenuated epithelial lesions of these mutants were correlated not only with reduced expression of the hyphal-associated gene SAP4, but also with the lack of SAP1 and SAP3 expression previously shown to be important for oral infections [19].
  • This observation was confirmed by a co-immunoprecipitation, which demonstrated that GM2AP and prosaposin are interactive partners of sortilin [6].

Analytical, diagnostic and therapeutic context of GM2A

  • From these data we developed a set of four PCR primers that can be used to identify GM2A mutations [20].
  • In the presence of GM2, a blue shift of the fluorescence emission maximum and a strong decrease of molar ellipticity values in circular dichroism spectra were observed only at pH 4.5 and at GM2/GM2AP molar ratio higher than 10:1 (up to 50:1) [17].
  • Surface plasmon resonance spectroscopy allowed the interaction of GM2AP with immobilized liposomes to be studied [21].
  • A three-step purification scheme was therefore devised consisting of Ni-NTA, reversed phase, and gel filtration chromatography, which finally yielded 10-12 mg of purified, monomeric GM2AP per liter of expression supernatant [21].


  1. The GM2 gangliosidoses databases: allelic variation at the HEXA, HEXB, and GM2A gene loci. Cordeiro, P., Hechtman, P., Kaplan, F. Genet. Med. (2000) [Pubmed]
  2. Refined mapping of the GM2 activator protein (GM2A) locus to 5q31.3-q33.1, distal to the spinal muscular atrophy locus. Heng, H.H., Xie, B., Shi, X.M., Tsui, L.C., Mahuran, D.J. Genomics (1993) [Pubmed]
  3. Characterization of an alternatively spliced GM2 activator protein, GM2A protein. An activator protein which stimulates the enzymatic hydrolysis of N-acetylneuraminic acid, but not N-acetylgalactosamine, from GM2. Wu, Y.Y., Sonnino, S., Li, Y.T., Li, S.C. J. Biol. Chem. (1996) [Pubmed]
  4. In vivo analysis of secreted aspartyl proteinase expression in human oral candidiasis. Naglik, J.R., Newport, G., White, T.C., Fernandes-Naglik, L.L., Greenspan, J.S., Greenspan, D., Sweet, S.P., Challacombe, S.J., Agabian, N. Infect. Immun. (1999) [Pubmed]
  5. Effect of GM2 activator protein on the enzymatic hydrolysis of phospholipids and sphingomyelin. Shimada, Y., Li, Y.T., Li, S.C. J. Lipid Res. (2003) [Pubmed]
  6. The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin. Lefrancois, S., Zeng, J., Hassan, A.J., Canuel, M., Morales, C.R. EMBO J. (2003) [Pubmed]
  7. Molecular analysis of a GM2-activator deficiency in two patients with GM2-gangliosidosis AB variant. Schepers, U., Glombitza, G., Lemm, T., Hoffmann, A., Chabas, A., Ozand, P., Sandhoff, K. Am. J. Hum. Genet. (1996) [Pubmed]
  8. Characterization of a recombinant molecule covalently indistinguishable from human cerebroside-sulfate activator protein (CSAct or Saposin B). Whitelegge, J.P., Ahn, V., Norris, A.J., Sung, H., Waring, A., Stevens, R.L., Fluharty, C.B., Prive, G., Faull, K.F., Fluharty, A.L. Cell. Mol. Biol. (Noisy-le-grand) (2003) [Pubmed]
  9. The complete amino-acid sequences of human ganglioside GM2 activator protein and cerebroside sulfate activator protein. Fürst, W., Schubert, J., Machleidt, W., Meyer, H.E., Sandhoff, K. Eur. J. Biochem. (1990) [Pubmed]
  10. The saposin-like proteins 1, 2, and 3 of Fasciola gigantica. Grams, R., Adisakwattana, P., Ritthisunthorn, N., Eursitthichai, V., Vichasri-Grams, S., Viyanant, V. Mol. Biochem. Parasitol. (2006) [Pubmed]
  11. Photoaffinity labelling of the human GM2-activator protein. Mechanistic insight into ganglioside GM2 degradation. Wendeler, M., Hoernschemeyer, J., Hoffmann, D., Kolter, T., Schwarzmann, G., Sandhoff, K. Eur. J. Biochem. (2004) [Pubmed]
  12. Differential expression of secreted aspartyl proteinases in a model of human oral candidosis and in patient samples from the oral cavity. Schaller, M., Schäfer, W., Korting, H.C., Hube, B. Mol. Microbiol. (1998) [Pubmed]
  13. Crystal structure of human GM2-activator protein with a novel beta-cup topology. Wright, C.S., Li, S.C., Rastinejad, F. J. Mol. Biol. (2000) [Pubmed]
  14. Candida albicans hyphal formation and the expression of the Efg1-regulated proteinases Sap4 to Sap6 are required for the invasion of parenchymal organs. Felk, A., Kretschmar, M., Albrecht, A., Schaller, M., Beinhauer, S., Nichterlein, T., Sanglard, D., Korting, H.C., Schäfer, W., Hube, B. Infect. Immun. (2002) [Pubmed]
  15. Evidence for lipid packaging in the crystal structure of the GM2-activator complex with platelet activating factor. Wright, C.S., Mi, L.Z., Rastinejad, F. J. Mol. Biol. (2004) [Pubmed]
  16. The sorting and trafficking of lysosomal proteins. Ni, X., Canuel, M., Morales, C.R. Histol. Histopathol. (2006) [Pubmed]
  17. Study of interaction of GM2 activator protein with GM2 using circular dichroism and fluorescence spectroscopy. Ravasi, D., Masserini, M., Vecchio, G., Li, Y.T., Li, S.C. Neurochem. Res. (2002) [Pubmed]
  18. Distribution of secreted aspartyl proteinases using a polymerase chain reaction assay with SAP specific primers in Candida albicans isolates. Kalkanci, A., Bozdayi, G., Biri, A., Kustimur, S. Folia Microbiol. (Praha) (2005) [Pubmed]
  19. Reduced expression of the hyphal-independent Candida albicans proteinase genes SAP1 and SAP3 in the efg1 mutant is associated with attenuated virulence during infection of oral epithelium. Korting, H.C., Hube, B., Oberbauer, S., Januschke, E., Hamm, G., Albrecht, A., Borelli, C., Schaller, M. J. Med. Microbiol. (2003) [Pubmed]
  20. Structure of the GM2A gene: identification of an exon 2 nonsense mutation and a naturally occurring transcript with an in-frame deletion of exon 2. Chen, B., Rigat, B., Curry, C., Mahuran, D.J. Am. J. Hum. Genet. (1999) [Pubmed]
  21. Expression of the GM2-activator protein in the methylotrophic yeast Pichia pastoris, purification, isotopic labeling, and biophysical characterization. Wendeler, M., Hoernschemeyer, J., John, M., Werth, N., Schoeniger, M., Lemm, T., Hartmann, R., Kessler, H., Sandhoff, K. Protein Expr. Purif. (2004) [Pubmed]
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