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Gene Review

AGA  -  aspartylglucosaminidase

Homo sapiens

Synonyms: AGU, ASRG, Aspartylglucosaminidase, GA, Glycosylasparaginase, ...
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Disease relevance of AGA


Psychiatry related information on AGA

  • The deficiency of a lysosomal enzyme, aspartylglucosaminidase, results in a lysosomal storage disorder, aspartylglucosaminuria, manifesting as progressive mental retardation [6].
  • Similar to the slow clinical course observed in human patients, the AGA -/- mice have behavioral symptoms that emerge at older age [7].
  • At the same time, AGA and AEMAb were assayed in 11 patients with infantile autism and 11 age- and sex-matched controls [8].
  • The AGA has a rapid response time (0-90% response = 160 ms for 10% He), is linear for helium concentration of 0.1-10%, is stable over a wide range of ambient temperatures, and is small and portable [9].
  • BACKGROUND: The pathogenesis of gait apraxia (GA) is unknown [10].

High impact information on AGA

  • The four currently known Ntn hydrolases (glutamine PRPP amidotransferase, penicillin acylase, the 20S proteasome and aspartylglucosaminidase) are encoded as inactive precursors, and are activated by cleavage of the peptide bond preceding the catalytic residue [11].
  • The suppression of NTH15 within cells at the flanks of the SAM permits GA biosynthesis, which promotes organized cell proliferation and consequently induces the determination of cell fate [12].
  • In this system, steroid treatment strictly induced NTH15 function and immediately suppressed the expression of a gibberellin (GA) biosynthetic gene encoding GA 20-oxidase (Ntc12) and also resulted in a decrease in bioactive GA levels [12].
  • AGA Institute Appoints New Editor of Clinical Gastroenterology and Hepatology [13].
  • Will Screening Colonoscopy Disappear and Transform Gastroenterology Practice? Threats to Clinical Practice and Recommendations to Reduce Their Impact: Report of a Consensus Conference Conducted by the AGA Institute Future Trends Committee [14].

Chemical compound and disease context of AGA

  • Hypoglycemia (blood glucose less than 20 mg./100 ml.) occurred in two SGA and one AGA infants [15].
  • The AGG and AGA are the least used arginine codons in E. coli but they are the most preferable ones in eukaryotes [16].
  • Lactate concentration and oxygen content were measured in 21 normal (AGA) and 34 intrauterine growth-retarded (IUGR) infants at the time of elective cesarean section [17].
  • The comparison of fetal to maternal leucine enrichment showed a progressive dilution of the fetal enrichment relative to the mother between AGA and IUGR of group 1 (0.89 versus 0.78, p < 0.02), group 2 (0.71, p < 0.001), and group 3 (0.62, p < 0.001), and also among the three IUGR groups [18].
  • AGA and IUGR fetuses with PI less than 4 SD have arterial lactate concentrations less than 2 mM even at low oxygen concentrations (O2 content less than 2 mM, O2 saturations less than 20%) [17].

Biological context of AGA

  • In this study we have characterized the phosphotransferase recognition signals of human lysosomal aspartylglucosaminidase (AGA) using transient expression of polypeptides carrying targeted amino acid substitutions [19].
  • Two of the lysines are especially important for the lysosomal targeting efficiency of AGA, which seems to be mostly dictated by the degree of phosphorylation of the alpha subunit oligosaccharide [19].
  • The intracellular consequences of the Ser72Pro mutation were analyzed by transient expression in COS-1 cells and we were able to demonstrate that this active-site mutation most probably does not destroy the enzyme activity per se, but specifically prevents the proteolytic activation cleavage of AGA in the endoplasmic reticulum (ER) [20].
  • Proper initial folding of AGA in the endoplasmic reticulum (ER) is dependent on intramolecular disulfide bridge formation and dimerization of two precursor polypeptides [1].
  • Here we used affinity-purified polyclonal antibodies against the native AGA and its denatured subunits to establish the molecular structure and intracellular location of the enzyme in normal and AGU fibroblasts [21].

Anatomical context of AGA


Associations of AGA with chemical compounds

  • Direct sequencing of amplified AGA cDNA from an AGU patient revealed a G----C transition resulting in the substitution of cysteine 163 with serine [22].
  • We found that three lysine residues and a tyrosine residing in three spatially distinct regions of the AGA polypeptide are necessary for phosphorylation of the oligosaccharides [19].
  • The polypeptide chain deduced from the AGA cDNA consists of 346 amino acids, has two potential N-glycosylation sites and 11 cysteine residues [22].
  • The subsequent activation of AGA occurs autocatalytically in the ER and the protein is transported via the Golgi to the lysosomal compartment using the mannose-6-phosphate receptor pathway [1].
  • Aspartylglucosaminidase (AGA, EC is an essential enzyme in the degradation of asparagine-linked glycoproteins [21].

Physical interactions of AGA


Regulatory relationships of AGA

  • Partial misincorporation of Lys for Arg has been observed for the Arg residues of IGF-1 when the molecule is expressed in Escherichia coli using a synthetic gene with the low frequency AGA codon encoding all six Arg residues and yeast preferred codons encoding the remaining residues [28].

Other interactions of AGA

  • Although both drugs equally target several sites, including AGA, we show that covalent modification of CGA is only achieved by ET729 [29].
  • The polymerase chain reaction was used to amplify the glycosylasparaginase protein coding sequence from the three AGU patients in order to compare them to the normal sequence from a full-length human placenta cDNA clone HPAsn.6 (Fisher, K.J., Tollersrud, O.K., and Aronson, N.N., Jr. (1990) FEBS Lett. 269, 440-444) [30].
  • After adjustment for age, height, body mass index, gender, smoking, and oral contraception, the mean IGF-I concentration and the mean IGF-I/IGFBP-3 ratio remained significantly lower in the SGA compared with the AGA group (P = 0.003 and P = 0.01, respectively) [31].
  • The coding sequence for t-PA revealed a significant proportion of AGA and AGG codons, which are rarely used in the coding sequences of E. coli [32].
  • The insulin-binding capacity was significantly increased in both the AGA and the LGA groups compared to the control, whereas the IGF-1 binding capacity was similar in the three groups [33].

Analytical, diagnostic and therapeutic context of AGA


  1. Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations. Saarela, J., Laine, M., Oinonen, C., Schantz , C., Jalanko, A., Rouvinen, J., Peltonen, L. Hum. Mol. Genet. (2001) [Pubmed]
  2. AGA technical review on obesity. Klein, S., Wadden, T., Sugerman, H.J. Gastroenterology (2002) [Pubmed]
  3. AGA Institute Technical Review on the Use of Endoscopic Therapy for Gastroesophageal Reflux Disease. Falk, G.W., Fennerty, M.B., Rothstein, R.I. Gastroenterology (2006) [Pubmed]
  4. AGA Future Trends Committee report: Colorectal cancer: a qualitative review of emerging screening and diagnostic technologies. Regueiro, C.R. Gastroenterology (2005) [Pubmed]
  5. AGA technical review on osteoporosis in gastrointestinal diseases. Bernstein, C.N., Leslie, W.D., Leboff, M.S. Gastroenterology (2003) [Pubmed]
  6. Toward understanding the neuronal pathogenesis of aspartylglucosaminuria: expression of aspartylglucosaminidase in brain during development. Uusitalo, A., Tenhunen, K., Heinonen, O., Hiltunen, J.O., Saarma, M., Haltia, M., Jalanko, A., Peltonen, L. Mol. Genet. Metab. (1999) [Pubmed]
  7. Monitoring the CNS pathology in aspartylglucosaminuria mice. Tenhunen, K., Uusitalo, A., Autti, T., Joensuu, R., Kettunen, M., Kauppinen, R.A., Ikonen, S., LaMarca, M.E., Haltia, M., Ginns, E.I., Jalanko, A., Peltonen, L. J. Neuropathol. Exp. Neurol. (1998) [Pubmed]
  8. Autism and celiac disease: failure to validate the hypothesis that a link might exist. Pavone, L., Fiumara, A., Bottaro, G., Mazzone, D., Coleman, M. Biol. Psychiatry (1997) [Pubmed]
  9. Use of an acoustic helium analyzer for measuring lung volumes. Krumpe, P.E., MacDannald, H.J., Finley, T.N., Schear, H.E., Hall, J., Cribbs, D. Journal of applied physiology: respiratory, environmental and exercise physiology. (1981) [Pubmed]
  10. A SPECT study of patients with gait apraxia without evidence of frontal lobe dysfunction. Chen, J.T., Fuh, J.L., Chen, C.C., Liu, R.S., Shan, D.E., Liao, K.K. Zhonghua Yi Xue Za Zhi (Taipei) (1998) [Pubmed]
  11. Autocatalytic processing of the 20S proteasome. Seemuller, E., Lupas, A., Baumeister, W. Nature (1996) [Pubmed]
  12. KNOX homeodomain protein directly suppresses the expression of a gibberellin biosynthetic gene in the tobacco shoot apical meristem. Sakamoto, T., Kamiya, N., Ueguchi-Tanaka, M., Iwahori, S., Matsuoka, M. Genes Dev. (2001) [Pubmed]
  13. AGA Institute Appoints New Editor of Clinical Gastroenterology and Hepatology. Lang, L. Gastroenterology (2006) [Pubmed]
  14. Will Screening Colonoscopy Disappear and Transform Gastroenterology Practice? Threats to Clinical Practice and Recommendations to Reduce Their Impact: Report of a Consensus Conference Conducted by the AGA Institute Future Trends Committee. Regueiro, C.R. Gastroenterology (2006) [Pubmed]
  15. Insulin and growth-hormone responses in neonatal hyperglycemia. Zarif, M., Pildes, R.S., Vidyasagar, D. Diabetes (1976) [Pubmed]
  16. Domains in human interferon alpha-1 gene containing tandems of arginine codons AGG play the role of translational initiators in E. coli. Alexandrova, R., Eweida, M., Georges, F., Dragulev, B., Abouhaidar, M.G., Ivanov, I. Int. J. Biochem. Cell Biol. (1995) [Pubmed]
  17. Lactate metabolism in normal and growth-retarded human fetuses. Marconi, A.M., Cetin, I., Ferrazzi, E., Ferrari, M.M., Pardi, G., Battaglia, F.C. Pediatr. Res. (1990) [Pubmed]
  18. Steady state maternal-fetal leucine enrichments in normal and intrauterine growth-restricted pregnancies. Marconi, A.M., Paolini, C.L., Stramare, L., Cetin, I., Fennessey, P.V., Pardi, G., Battaglia, F.C. Pediatr. Res. (1999) [Pubmed]
  19. Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase. Tikkanen, R., Peltola, M., Oinonen, C., Rouvinen, J., Peltonen, L. EMBO J. (1997) [Pubmed]
  20. Ser72Pro active-site disease mutation in human lysosomal aspartylglucosaminidase: abnormal intracellular processing and evidence for extracellular activation. Peltola, M., Tikkanen, R., Peltonen, L., Jalanko, A. Hum. Mol. Genet. (1996) [Pubmed]
  21. Human aspartylglucosaminidase. A biochemical and immunocytochemical characterization of the enzyme in normal and aspartylglucosaminuria fibroblasts. Enomaa, N., Heiskanen, T., Halila, R., Sormunen, R., Seppälä, R., Vihinen, M., Peltonen, L. Biochem. J. (1992) [Pubmed]
  22. Aspartylglucosaminuria: cDNA encoding human aspartylglucosaminidase and the missense mutation causing the disease. Ikonen, E., Baumann, M., Grön, K., Syvänen, A.C., Enomaa, N., Halila, R., Aula, P., Peltonen, L. EMBO J. (1991) [Pubmed]
  23. Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL). Lehtovirta, M., Kyttälä, A., Eskelinen, E.L., Hess, M., Heinonen, O., Jalanko, A. Hum. Mol. Genet. (2001) [Pubmed]
  24. Expression of aspartylglucosaminidase in human tissues from normal individuals and aspartylglucosaminuria patients. Enomaa, N.E., Lukinmaa, P.L., Ikonen, E.M., Waltimo, J.C., Palotie, A., Paetau, A.E., Peltonen, L. J. Histochem. Cytochem. (1993) [Pubmed]
  25. Localization of the disulfide bond involved in post-translational processing of glycosylasparaginase and disrupted by a mutation in the Finnish-type aspartylglycosaminuria. McCormack, A.L., Mononen, I., Kaartinen, V., Yates, J.R. J. Biol. Chem. (1995) [Pubmed]
  26. Characterization of three alleles causing aspartylglycosaminuria: two from a British family and one from an American patient. Park, H., Vettese, M.B., Fensom, A.H., Fisher, K.J., Aronson, N.N. Biochem. J. (1993) [Pubmed]
  27. Comparison of the prevalence of glutamic acid decarboxylase (GAD65) and gliadin antibodies (AGA) in a randomly selected adult estonian population. Uibo, R., Sullivan, E.P., Uibo, O., Lernmark, A., Salur, L., Kivik, T., Mandel, M. Horm. Metab. Res. (2001) [Pubmed]
  28. Mistranslation in IGF-1 during over-expression of the protein in Escherichia coli using a synthetic gene containing low frequency codons. Seetharam, R., Heeren, R.A., Wong, E.Y., Braford, S.R., Klein, B.K., Aykent, S., Kotts, C.E., Mathis, K.J., Bishop, B.F., Jennings, M.J. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
  29. Further insight into the DNA recognition mechanism of trabectedin from the differential affinity of its demethylated analogue ecteinascidin ET729 for the triplet DNA binding site CGA. Marco, E., David-Cordonnier, M.H., Bailly, C., Cuevas, C., Gago, F. J. Med. Chem. (2006) [Pubmed]
  30. Characterization of the mutation responsible for aspartylglucosaminuria in three Finnish patients. Amino acid substitution Cys163----Ser abolishes the activity of lysosomal glycosylasparaginase and its conversion into subunits. Fisher, K.J., Aronson, N.N. J. Biol. Chem. (1991) [Pubmed]
  31. Smallness for gestational age is associated with persistent change in insulin-like growth factor I (IGF-I) and the ratio of IGF-I/IGF-binding protein-3 in adulthood. Verkauskiene, R., Jaquet, D., Deghmoun, S., Chevenne, D., Czernichow, P., Lévy-Marchal, C. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  32. The production of improved tissue-type plasminogen activator in Escherichia coli. Mattes, R. Semin. Thromb. Hemost. (2001) [Pubmed]
  33. Insulin-receptor kinase is enhanced in placentas from non-insulin-dependent diabetic women with large-for-gestational-age babies. Takayama-Hasumi, S., Yoshino, H., Shimisu, M., Minei, S., Sanaka, M., Omori, Y. Diabetes Res. Clin. Pract. (1994) [Pubmed]
  34. A novel aspartylglucosaminuria mutation affects translocation of aspartylglucosaminidase. Saarela, J., von Schantz, C., Peltonen, L., Jalanko, A. Hum. Mutat. (2004) [Pubmed]
  35. Cloning and sequence analysis of a cDNA for human glycosylasparaginase. A single gene encodes the subunits of this lysosomal amidase. Fisher, K.J., Tollersrud, O.K., Aronson, N.N. FEBS Lett. (1990) [Pubmed]
  36. Production of antiendomysial antibodies after in-vitro gliadin challenge of small intestine biopsy samples from patients with coeliac disease. Picarelli, A., Maiuri, L., Frate, A., Greco, M., Auricchio, S., Londei, M. Lancet (1996) [Pubmed]
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