Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20645 (mannose-6-phosphate receptor)
 320 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aspartylglycosaminuria (AGU) is the most common disorder of glycoprotein degradation. AGU patients are deficient in glycosylasparaginase (GA), which results in accumulation of aspartylglucosamine in body fluids and tissues. Human glycosylasparaginase was stably overexpressed in NIH-3T3 mouse fibroblasts, in which the unusual posttranslational processing and maturation of the enzyme occurred in a high degree. The recombinant enzyme was isolated as two isoforms, which were both phosphorylated, and actively transported into AGU fibroblasts and lymphoblasts through mannose-6-phosphate receptor-mediated endocytosis. The rate of uptake into fibroblasts was half-maximal when the concentration of GA in the medium was 5 x 10(-8) M. Immunofluorescence microscopy suggested compartmentalization of the recombinant enzyme in the lysosomes. Supplementation of culture medium with either isoform cleared AGU lymphoblasts of stored aspartylglucosamine when glycosylasparaginase activity in the cells reached 3-4% of that in normal lymphoblasts. A relatively small amount of recombinant GA in the culture medium was sufficient to reverse pathology in the target cells, indicating high corrective quality of the enzyme preparations. The combined evidence indicates that enzyme replacement therapy with the present recombinant glycosylasparaginase might reverse pathology at least in somatic cells of AGU patients.
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PMID:Recombinant glycosylasparaginase and in vitro correction of aspartylglycosaminuria. 789 15

A deficiency of functional aspartylglucosaminidase (AGA) causes a lysosomal storage disease, aspartylglucosaminuria (AGU). The recessively inherited disease is enriched in the Finnish population, where 98% of AGU alleles contain one founder mutation, AGU(Fin). Elsewhere in the world, we and others have described 18 different sporadic AGU mutations. Many of these are predicted to interfere with the complex intracellular maturation and processing of the AGA polypeptide. Proper initial folding of AGA in the endoplasmic reticulum (ER) is dependent on intramolecular disulfide bridge formation and dimerization of two precursor polypeptides. 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. Here we use the three-dimensional structure of AGA to predict structural consequences of AGU mutations, including six novel mutations, and make an effort to characterize every known disease mutation by dissecting the effect of mutations on intracellular stability, maturation, transport and the activity of AGA. Most mutations are substitutions replacing the original amino acid with a bulkier residue. Mutations of the dimer interface prevent dimerization in the ER, whereas active site mutations not only destroy the activity but also affect maturation of the precursor. Depending on their effects on the AGA polypeptide the mutations can be categorized as mild, moderate or severe. These data contribute to the expanding body of knowledge pertaining to molecular pathogenesis of AGU.
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PMID:Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations. 1130 71

Aspartylglycosaminuria (AGU), a severe lysosomal storage disease, is caused by the deficiency of the lysosomal enzyme, glycosylasparaginase (GA), and accumulation of aspartylglucosamine (GlcNAc-Asn) in tissues. Here we show that human leukocyte glycosylasparaginase can correct the metabolic defect in Epstein-Barr virus (EBV)-transformed AGU lymphocytes rapidly and effectively by mannose-6-phosphate receptor-mediated endocytosis or by contact-mediated cell-to-cell transfer from normal EBV-transformed lymphocytes, and that 2-7% of normal activity is sufficient to correct the GlcNAc-Asn metabolism in the cells. Cell-to-cell contact is obligatory for the transfer of GA since normal transformed lymphocytes do not excrete GA into extracellular medium. The combined evidence indicates that cell-to-cell transfer of GA plays a main role in enzyme replacement therapy of AGU by normal lymphocytes.
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PMID:Human leukocyte glycosylasparaginase: cell-to-cell transfer and properties in correction of aspartylglycosaminuria. 1141 16