Disease relevance of AGA

• A deficiency of functional aspartylglucosaminidase (AGA) causes a lysosomal storage disease, aspartylglucosaminuria (AGU) [1].
• AGA technical review on obesity [2].
• AGA Institute Technical Review on the Use of Endoscopic Therapy for Gastroesophageal Reflux Disease [3].
• AGA Future Trends Committee report: Colorectal cancer: a qualitative review of emerging screening and diagnostic technologies [4].
• AGA technical review on osteoporosis in gastrointestinal diseases [5].

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

• Transient expression of this cDNA in COS-1 cells resulted in increased expression of immunoprecipitable AGA protein [22].
• Furthermore, in polarized epithelial Caco-2 cells, PPT is localized exclusively to the basolateral site, in contrast to the classical lysosomal enzyme, aspartylglucosaminidase (AGA), which is localized in the apical site [23].
• In tissues from AGU patients, AGA immunoreactivity could be detected in hepatocytes and in proximal tubule cells but not in the pyramidal cells [24].
• To localize the potential disulfide bonds, the isolated heavy chain of human leukocyte glycosylasparaginase was treated with the enzyme alpha-chymotrypsin, and the resulting peptides were separated by high performance liquid chromatography prior to and after reduction and S-carboxymethylation [25].
• Expression in COS-1 cells revealed the paternal Ala-->Val amino-acid substitution destroyed glycosylasparaginase catalytic activity, prevented transport of the mutant protein to the lysosome, and prevented maturation of the enzyme precursor to its native subunit structure [26].

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 3.5.1.26) is an essential enzyme in the degradation of asparagine-linked glycoproteins [21].

Physical interactions of AGA

• IgG-type glutamic acid decarboxylase (GAD65) antibodies were determined using radioligand-binding assay and IgG/IgA-type gliadin antibodies (AGA) by enzyme-linked immunosorbent assay [27].

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

• The L15R AGA protein was only faintly detectable by immunofluorescence analysis and observed in the endoplasmic reticulum [34].
• Metabolic labeling and immunoprecipitation revealed only a small amount of AGA polypeptides but the specific activity of the mutant enzyme was surprisingly high, 37% of the wild type [34].
• Use of the PCR determined the glycosylasparaginase cDNA sequence from both parents of the British patient and his AGU-affected brother [26].
• Cloning and sequence analysis of a cDNA for human glycosylasparaginase. A single gene encodes the subunits of this lysosomal amidase [35].
• EMA and AGA were detected in the supernatants of these organ culture biopsy samples by ELISA and immunofluorescence technique, respectively [36].

References