Disease relevance of Gcs1

• Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-alpha-glucosidase [1].
• Muscle as a putative producer of acid alpha-glucosidase for glycogenosis type II gene therapy [2].
• Glycogen storage disease type II (GSDII; Pompe disease), caused by inherited deficiency of acid alpha-glucosidase, is a lysosomal disorder affecting heart and skeletal muscles [3].
• Using this model, we investigated the delivery of recombinant adeno-associated virus (rAAV) vectors encoding the human GAA cDNA to the developing embryo [4].
• Castanospermine, a recently discovered inhibitor of glucosidase I, was tested for its effect on experimental metastasis of B16-F10 murine melanoma cells and was compared to treatment with swainsonine and tunicamycin [5].

High impact information on Gcs1

• Here we describe the action of 1-deoxymannojirimycin (1,5-dideoxy-1,5-imino-D-mannitol, dMM; Fig. 1) on the biosynthesis of IgM and IgD. dMM is the mannose analogue of 1-deoxynojirimycin (dNM; Fig. 1), itself a glucosidase inhibitor [6].
• Persistent glycoprotein misfolding activates the glucosidase II/UGT1-driven calnexin cycle to delay aggregation and loss of folding competence [7].
• Perturbation of the folding environment in intact cells with the reducing agent dithiothreitol or the trimming glucosidase inhibitor N-7-oxadecyl-deoxynojirimycin prolongs the presence of mAb-reactive K(b) heavy chains [8].
• Consistent with a requirement for glucose (Glc) trimming for survival of nascent TCR alpha proteins within the ER, we found that newly synthesized TCR alpha chains were innately unstable in the glucosidase II-deficient BW5147 mutant cell line PHAR2 [9].
• We found that treatment of BW5147 T cells with the glucosidase inhibitor castanospermine resulted in markedly accelerated degradation of nascent TCR alpha proteins with a half-life of approximately 20 min [9].

Chemical compound and disease context of Gcs1

• A lectin-resistant mouse lymphoma cell line is deficient in glucosidase II, a glycoprotein-processing enzyme [10].
• We have made transgenic lines expressing human GAA in skeletal and cardiac muscle of Gaa(-/-) mice, and we turned the transgene on at different stages of disease progression by using a tetracycline-controllable system [11].
• The effect of castanospermine on the processing of N-linked oligosaccharides was examined in the parent mouse lymphoma cell line and in a mutant cell line that lacks glucosidase II [12].
• NB-DNJ, however, exhibits adverse effects at high doses such as weight loss and GI tract distress (due to glucosidase inhibition) [13].
• An increase in cohydrolase level resulted from injection of phenylhydrazine, which produces hemolysis and consequently an increased workload for the glucosidase of liver [14].

Biological context of Gcs1

• A single point mutation (TCC to TTC; Ser to Phe) was identified in Lec23 Gcs1 cDNA and genomic DNA [15].
• The major transcript for glucosidase I on northern blot appeared to be 3.1 kb; Southern blotting and DNA sequencing indicated the size of the gene to be 6.8 kb, comprising four exons separated by three introns [16].
• The glucosidase inhibitors nojirimycin (NM) and 1-deoxynojirimycin (dNM) interfere with N-linked glycosylation [17].
• The enzymatic defect in GSD II results from mutations in the acid alpha-glucosidase (GAA) gene, which encodes a 76 kDa protein involved in intralysosomal glycogen hydrolysis [2].
• Glycogen storage disease type II (GSDII), caused by a deficiency in acid alpha-glucosidase (GAA), leads to lysosomal accumulation of glycogen in all cell types and abnormal myofibrillogenesis in striated muscle [4].

Anatomical context of Gcs1

• Both enzymes were recovered in membranes that were less dense than the membranes containing the endoplasmic reticulum marker enzymes, glucosidase I and II [18].
• Subsequently, systemic distribution and uptake of the proenzyme into the skeletal and cardiac muscles of the GAA-knockout mouse was confirmed [1].
• We detected a strong expression of GAA in the injected muscle, secretion into plasma, and uptake by peripheral skeletal muscle and the heart [2].
• We previously reported the use of an adenovirus vector expressing GAA (AdGAA) for the transduction of myoblasts and myotubes cultures from GSD II patients [2].
• A mouse model of this disease was obtained by targeted disruption of the murine acid alpha-glucosidase gene (Gaa) in embryonic stem cells [3].

Associations of Gcs1 with chemical compounds

• Glucosidase I initiates the processing of asparagine (N-) linked glycoproteins by removing the distal alpha1,2-linked glucosyl residue of the tetradecasaccharide Glc(3)Man(9)GlcNAc(2) [16].
• Glucosidase inhibitors such as NM and dNM, as well as the mannosidase inhibitor SW, allow modification of glycan structure, and may be used to study the biological role of glycoprotein oligosaccharides and their modifications [17].
• Effects of the glucosidase inhibitors nojirimycin and deoxynojirimycin on the biosynthesis of membrane and secretory glycoproteins [17].
• Furthermore, using tetracycline regulation, we somatically induced human GAA in the knockout mice, and demonstrated that the skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early [19].
• Castanospermine and the glucosidase inhibitor N-methyldeoxynojirimycin prevented the morphological differentiation of endothelial cells in vitro [20].

Regulatory relationships of Gcs1

• Maturation of gp100 into 150-180-kDa CBI-gp was inhibited if BF were chased in the presence of glucosidase inhibitors castanospermine or deoxynojirimycin [21].

Other interactions of Gcs1

• We have further regionally localized the gene for human acid alpha glucosidase (GAA) to 17q21----q23 by examination of hybrid clones derived from a fusion between human fibroblasts carrying a 17/19 balanced translocation (17pter----17q23::19p13.3----19pter; 19qter----p13.3::17q23----17qter) and a mouse line deficient in thymidine kinase [22].
• The role of glucosylated oligosaccharides in the biogenesis of the glycoprotein (G protein) of vesicular stomatitis virus was studied in PhaR2.7, a mouse lymphoma cell line deficient in glucosidase II activity [23].
• Of the glycosidic enzymes evaluated, glucuronidase (1000 micrograms/ml) caused significant inhibition of sperm binding but not sperm penetration, and glucosidase, galactosidase, and neuraminidase had no effect on either sperm attachment or sperm penetration [24].
• alpha-Glucosidase inhibitors prevent diet-induced increases in intestinal sugar transport in diabetic mice [25].
• The hearts were excised, homogenized, and the following enzymatic activities measured: N-Acetyl-beta-glucosaminidase, N-acetyl-beta-galactosaminidase, beta-glucosaminidase, aryl sulphatase, alpha-mannosidase, alpha-glucosidase, beta-galactosidase, beta glucosidase, total p-nitrophenyl phosphatase, acid phosphatase and 5'-phosphodiesterase type IV [26].

Analytical, diagnostic and therapeutic context of Gcs1

• Thus, by rocket immunoelectrophoresis, cells transformed with human DNA yielded a "rocket" which reacted with antibody to human but not to mouse glucosidase II and which hydrolyzed substrate in situ [27].
• By in situ hybridization with GAA antisense mRNA, low signals were detected in most tissues throughout gestation [28].
• Amino acid sequencing of the 80-kDa protein, followed by molecular cloning, revealed high homology to human and bovine cDNAs postulated to encode the beta-subunit of glucosidase II [29].
• Persistent expression of vector-derived human GAA was observed in BALB/c mice up to 6 months after treatment [30].
• After converting the liver into a "depot" organ, we found that intravenous injection of the [E1-,polymerase-]AdGAA vector allowed for hepatic secretion of GAA over an at least 20-fold dosage range [31].

References