Biosynthesis of human α-N-acetylgalactosaminidase: Defective phosphorylation and maturation in infantile α-NAGA deficiency

Hu, P.; Reuser, Arnold; Janse, H.C.; Kleijer, Wim J.; Schindler, Detlev; Sakuraba, Hitoshi; Tsuji, Akihiko; Suzuki, Yoshiyuki; Diggelen, O. P. van

doi:10.1016/0006-291x(91)91678-6

Cited by 10 publications

(3 citation statements)

References 19 publications

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“…In certain cases of glycogenosis I1278, Sandhoff disease 66 and Gui-gangliosidosis 146'2i9, a-N-acetylgalactosaminidase deficiency i49 and fucosidosis 62'i61, mutations have been described that impair the maturation of the precursors, most probably by affecting their transport competence. The impaired transport also precludes the phosphorylation of the precursors 149,270,278 Conditions that interfere with lysosomal acidification or with the intracellular transport also affect the processing of lysosomal enzymes. This was shown initially for flhexosaminidase and a-glucosidase in fibroblasts that had been treated with NH4C1 or chloroquine i26…”

Section: Exoproteolytic Maturation Upon Fragmentation Addi-mentioning

confidence: 98%

Theearly andlate processing of lysosomal enzymes: Proteolysis and compartmentation

1992

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Lysosomal enzymes are subjected to a number of modifications including carbohydrate restructuring and proteolytic maturation. Some of these reactions support lysosomal targeting, others are necessary for activation or keeping the enzyme inactive before being segregated, while still others may be adventitious. The non-segregated fraction of the enzyme is secreted and can be isolated from the medium. It is considered that the secreted lysosomal enzymes fulfill certain physiological and pathophysiological roles. By comparing the secreted and the intracellular enzymes it is possible to distinguish between the reactions that occur before and after the segregation. In this review the reactions that may influence the segregation are referred to as the early processing and those characteristic for the enzymes isolated from lysosomal compartments as the late processing. The early processing is characterized mainly by modifications of carbohydrate side chains. In the late processing, proteolytic fragmentation represents the most conspicuous changes. The review focuses on the compartmentation of the reactions and the proteolytic fragmentation of lysosomal enzyme precursors. While a plethora of proteolytic reactions are involved, our knowledge of the proteinases responsible for the particular maturation reactions remains very limited. The review points also to work with cells from patients affected with lysosomal storage disorders, which contributed to our understanding of the lysosomal apparatus.

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Section: Exoproteolytic Maturation Upon Fragmentation Addi-mentioning

confidence: 98%

Theearly andlate processing of lysosomal enzymes: Proteolysis and compartmentation

1992

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“…19 NAGA-degrading activity was fluorometrically measured with MU-a-D-N-acetylgalactosamine (MU-2-acetamide-2-deoxy-a-D-galactopyranoside; Toronto Research Chemicals, North York, ON, Canada) as a substrate. 20 Both the GLA and the NAGA assay were conducted with a Wallac 1420 ARVO MX multilabel counter (Perkin Elmer, Waltham, MA) at excitation and emission wavelengths of 355 nm and 460 nm, respectively. Protein concentrations were determined with a Micro BCA Protein Assay Reagent Kit (PIERCE, Rockfold, IL), and bovine serum albumin was used as a standard.…”

Section: Gla and Naga Assays And Protein Determinationmentioning

confidence: 99%

Use of a Modified α-N-Acetylgalactosaminidase in the Development of Enzyme Replacement Therapy for Fabry Disease

Tajima

Kawashima

Tsukimura

et al. 2009

The American Journal of Human Genetics

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A modified alpha-N-acetylgalactosaminidase (NAGA) with alpha-galactosidase A (GLA)-like substrate specificity was designed on the basis of structural studies and was produced in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-alpha-D-galactopyranoside. It retained the original NAGA's stability in plasma and N-glycans containing many mannose 6-phosphate (M6P) residues, which are advantageous for uptake by cells via M6P receptors. There was no immunological cross-reactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease recurrently treated with a recombinant GLA. The enzyme cleaved globotriaosylceramide (Gb3) accumulated in cultured fibroblasts from a patient with Fabry disease. Furthermore, like recombinant GLA proteins presently used for enzyme replacement therapy (ERT) for Fabry disease, the enzyme intravenously injected into Fabry model mice prevented Gb3 storage in the liver, kidneys, and heart and improved the pathological changes in these organs. Because this modified NAGA is hardly expected to cause an allergic reaction in Fabry disease patients, it is highly promising as a new and safe enzyme for ERT for Fabry disease.

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“…Studies on patients with lysosomal storage disorders have also implicated the RER in the retention of mutant lysosomal enzymes, including β-hexosaminidase in Tay-Sachs disease [24][25][26], α-N-acetylgalactosaminidase in Schindler's disease [27] and α--glucosidase in Pompe's disease [28]. In MPS VI patients, low levels of conformationally altered 4-sulphatase protein have been reported, corresponding to less than 5 % of the catalytic capacity of normal human controls [14,16,20].…”

Section: Figure 3 Localization Of C91 and C91t In Cho Cellsmentioning

confidence: 99%

Processing of normal lysosomal and mutant N-acetylgalactosamine 4-sulphatase: BiP (immunoglobulin heavy-chain binding protein) may interact with critical protein contact sites

BRADFORD¹,

GETHING²,

DAVEY³

et al. 1999

Biochem. J.

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The lysosomal hydrolase N-acetylgalactosamine-4-sulphatase (4-sulphatase) is essential for the sequential degradation of the glycosaminoglycans, dermatan and chondroitin sulphate and, when deficient, causes the lysosomal storage disorder mucopolysaccharidosis type VI. The cysteine at codon 91 of human 4-sulphatase was identified previously as a key residue in the active site of the enzyme and was mutated by site-directed mutagenesis to produce a 4-sulphatase in which cysteine-91 was replaced by a threonine residue (C91T). The C91T mutation caused a loss of 4-sulphatase activity, a detectable protein conformational change and a lower level of intracellular 4-sulphatase protein [Brooks, Robertson, Bindloss, Litjens, Anson, Peters, Morris and Hopwood (1995) Biochem. J. 307, 457-463]. In the present study, we report that C91T is synthesized normally in the endoplasmic reticulum as a 66 kDa glycosylated protein, which is very similar in size to wild-type 4-sulphatase. However, C91T neither underwent normal Golgi processing, shown by lack of modification to form mannose 6-phosphate residues on its oligosaccharide side chains, nor did it traffic to the lysosome to undergo normal endosomal-lysosomal proteolytic processing. Instead, C91T remained in an early biosynthetic compartment and was degraded. The molecular chaperone, immunoglobulin binding protein (BiP), was associated with newly-synthesized wild-type and mutant 4-sulphatase proteins for extended periods, but no direct evidence was found for involvement of BiP in the retention or degradation of the C91T protein. This suggested that prolonged association of mutant protein with BiP does not necessarily infer involvement of BiP in the quality control process, as previously implied in the literature. The predicted BiP binding sites on 4-sulphatase map to beta-strands and alpha-helices, which are co-ordinated together in the folded molecule, indicating that BiP interacts with critical protein folding or contact sites on 4-sulphatase.

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Biosynthesis of human α-N-acetylgalactosaminidase: Defective phosphorylation and maturation in infantile α-NAGA deficiency

Cited by 10 publications

References 19 publications

Theearly andlate processing of lysosomal enzymes: Proteolysis and compartmentation

Theearly andlate processing of lysosomal enzymes: Proteolysis and compartmentation

Use of a Modified α-N-Acetylgalactosaminidase in the Development of Enzyme Replacement Therapy for Fabry Disease

Processing of normal lysosomal and mutant N-acetylgalactosamine 4-sulphatase: BiP (immunoglobulin heavy-chain binding protein) may interact with critical protein contact sites

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