Activating Compound | Comment | Organism | Structure |
---|---|---|---|
additional information | processing and activation of aspartylglucosaminidase by autocatalytic cleavage, overview | Homo sapiens |
Application | Comment | Organism |
---|---|---|
medicine | use of codon-optimized AGA may be beneficial for the therapy options in treatment of the lysosomal storage disorder aspartylglucosaminuria (AGU) | Homo sapiens |
Cloned (Comment) | Organism |
---|---|
gene AGA, DNA and amino acid sequence determination and analysis, genomic organization of Aurelia gene AGA and exon-intron structure, molecular phylogenetic analysis based on the nucleotide sequences of N-terminal nucleophile (Ntn)_asparaginase_2_like superfamily genes, quantitative real-time PCR enzyme expresssion analysis | Aurelia aurita |
gene AGA, genotyping, recombinant expression of codon-optimized genes encoding enzyme variants S149 and T149 in HEK-293T and HeLa cells, the Thr149 variant exhibits a slightly higher expression level than the Ser149 variant. Recombinant expression of AGA variants in transgenic patient fibroblasts, both wild-type and AGUFin-major mutant type. The transfection with the AGA variants improves the lysosomal morphology in AGU fibroblasts, low transfection efficiency | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
additional information | single nucleotide polymorphism rs2228119 (NM_000027.3:c.446C>G - p.(Thr149Ser)) results in amino acid variation Ser vs. Thr at position 149 (base and amino acid variation in red) of the human AGA enzyme. Functional analysis of the Ser149/Thr149 variants of human aspartylglucosaminidase and optimization of the coding sequence for protein production. Codon-optimized versions of the two variants are expressed at significantly higher levels than AGA with the natural codon-usage. The second most common allele in Finland is a 2 bp deletion called AGUFin-minor (NM_000027.3; c.199_200del - p.Glu67fc*3). Genotype frequency of single nucleotide polymorphism (SNP) rs2228119 in various populations | Homo sapiens |
R161Q/C163S | naturally occuring mutation, the AGUFin-major mutation is a combination of two missense mutations, abolishing a disulfide bond and destabilizing the AGA structure. The pathogenic C163S substitution is always combined with a functionally neutral Arg161Gln substitution. Mutations in the AGA gene result in aspartylglucosaminuria (AGU, OMIM 208400), a lysosomal storage disorder that is characterized by progressive loss of intellectual capabilities and some skeletal abnormalities. AGU patients are born seemingly normal, but the progressive course of the disease manifests in, e.g. developmental delay, loss of speech and coarse facial features early in childhood. In adulthood, most AGU patients are severely retarded and require special care | Homo sapiens |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
bafilomycin A1 | - |
Aurelia aurita | |
Chloroquine | - |
Aurelia aurita |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
lysosome | - |
Homo sapiens | 5764 | - |
lysosome | in the lysosomes, the C-termini of both alpha- and beta-subunits are trimmed by proteases, resulting in the mature form of AGA, though these trimming steps are not necessary for the catalytic activity of AGA | Aurelia aurita | 5764 | - |
additional information | Aurelia AGA possesses an N-terminal signal peptide | Aurelia aurita | - |
- |
additional information | the pro-enzyme contains a 23 residues signal peptide | Homo sapiens | - |
- |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Aurelia aurita | - |
clonal polyp strains established from adult female Aurelia jellyfish captured in the Seto Inland Sea | - |
Homo sapiens | P20933 | Finnish population | - |
Posttranslational Modification | Comment | Organism |
---|---|---|
glycoprotein | AGA contains two glycosylation sites at Asn38 and Asn308 | Homo sapiens |
glycoprotein | Aurelia AGA possesses potential N-glycosylation sites, Asn36, Asn48, Asn168, and Asn213 | Aurelia aurita |
proteolytic modification | in the lysosomes, the C-termini of both alpha- and beta-subunits are trimmed by proteases, resulting in the mature form of AGA, though these trimming steps are not necessary for the catalytic activity of AGA | Aurelia aurita |
proteolytic modification | processing and activation of aspartylglucosaminidase by autocatalytic cleavage, overview. AGA is synthesized in the endoplasmic reticulum as a 346 amino acid (aa) polypeptide from which 23 residues of the signal peptide are removed. Very soon after synthesis in the endoplasmic reticulum, two AGA precursors homodimerize, inducing an autocatalytic cleavage of both precursors N-terminally to Thr206 into 27 kDa pro-alpha and 17 kDa subunits. After transport to lysosomes, the pro-alpha is C-terminally cleaved into 24 kDa mature alpha-subunit, whereas processing of the beta-subunit gives rise to the 14 kDa beta'-subunit. Neither of these lysosomal processing steps displays an effect on the enzyme activity | Homo sapiens |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
ephyra | moderate expression level | Aurelia aurita | - |
additional information | AGA expression increases during strobilation, and is then decreased in medusae | Aurelia aurita | - |
polyp | low expression level | Aurelia aurita | - |
strobila | high expression level | Aurelia aurita | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
additional information | processing and activation of aspartylglucosaminidase by autocatalytic cleavage, overview | Homo sapiens | ? | - |
? |
Subunits | Comment | Organism |
---|---|---|
heterotetramer | (alphabeta)2 | Aurelia aurita |
Synonyms | Comment | Organism |
---|---|---|
AGA | - |
Homo sapiens |
AGA | - |
Aurelia aurita |
aspartylglucosaminidase | - |
Homo sapiens |
aspartylglucosaminidase | - |
Aurelia aurita |
General Information | Comment | Organism |
---|---|---|
evolution | belongs to the group of so-called N-terminal nucleophile (NTN) hydrolases. The members of the NTN hydrolase family, which in addition to AGA also include, e.g., the proteasome beta-subunit and penicillin acylase, show very little similarity at the amino acid sequence level, but they exhibit a highly similar folded structure | Homo sapiens |
evolution | molecular phylogenetic analysis of aspartylglucosaminidases | Aurelia aurita |
malfunction | defects in the AGA gene result in a lysosomal storage disorder, aspartylglucosaminuria (AGU), that manifests mainly as progressive mental retardation. A number of AGU missense mutations have been identified that result in reduced AGA activity. Human variants contain either Ser or Thr in position 149, and Thr149 AGA, which is the rare variant, can be considered as a neutral or benign variant. AGU mutations result in reduced AGA activity in patient cells. Mutations in the AGA gene result in aspartylglucosaminuria (AGU, OMIM 208400), a lysosomal storage disorder that is characterized by progressive loss of intellectual capabilities and some skeletal abnormalities. AGU patients are born seemingly normal, but the progressive course of the disease manifests in, e.g., developmental delay, loss of speech and coarse facial features early in childhood. In adulthood, most AGU patients are severely retarded and require special care | Homo sapiens |
malfunction | lysosomal acidification inhibitors, chloroquine or bafilomycin A1, disturb medusa morphogenesis at the oral end, suggesting involvement of lysosomal hydrolases in strobilation | Aurelia aurita |
additional information | AGA belongs to the group of so-called N-terminal nucleophile (NTN) hydrolases, as the free alpha-amino group of Thr206 is involved in the catalysis as the base, whereas the OH group of Thr206 functions as a nucleophile during the catalysis | Homo sapiens |
physiological function | aspartylglucosaminidase (AGA) is a lysosomal hydrolase that participates in the breakdown of glycoproteins | Homo sapiens |
physiological function | the life cycle of the moon jellyfish, Aurelia aurita, alternates between a benthic asexual polyp stage and a planktonic sexual medusa (jellyfish) stage. Transition from polyp to medusa is called strobilation. Aspartylglucosaminidase (AGA), a lysosomal hydrolase, is upregulated during strobilation | Aurelia aurita |