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PubMed1984

The application of the Milner-Avigad method for the quantitative determination of endouronidase activities.

The Milner-Avigad method (Milner, Y. and Avigad, G. (1967) Carbohydr. Res. 4, 359-361) has been shown to have high specificity for measuring the reducing powers of free hexuronic acids; its applicability in the quantitative determination of endouronidase activity was the purpose of this investigation. Among the constituent monosaccharides of glycosaminoglycans, hexuronic acids showed high color yield by this method, while xylose, galactose and N-acetylhexosamine recorded negligible color yield. Among the monosaccharide residues at the reducing terminals of oligosaccharides, only hexuronic acids exhibited color yield. However, the color yield was less than that of free hexuronic acids. Gel filtration chromatography of reaction products revealed that the cleavage of the oligosaccharide chains and the resultant exposure of new reducing terminals were not caused by the reaction procedures involved in this method. These data indicate that the Milner-Avigad method is useful for determining the presence of hexuronic acid residues preferentially at reducing terminals of glycosaminoglycan moieties. Thus, it supported the conclusion that the Milner-Avigad method is applicable for the quantitative determination of endouronidase activity using glycosaminoglycan as a substrate.

Animals↗
PubMed2006

Stabilising normal and mis-sense variant alpha-glucosidase.

alpha-Glucosidase (EC 3.2.1.3) is a lysosomal enzyme that hydrolyses alpha-1,4- and alpha-1,6-linkages of glycogen to produce free glucose. A deficiency in alpha-glucosidase activity results in glycogen storage disorder type II (GSD II), also called Pompe disease. Here, d-glucose was shown to be a competitive inhibitor of alpha-glucosidase and when added to culture medium at 6.0 g/L increased the production of this protein by CHO-K1 expression cells and stabilised the enzyme activity. D-Glucose also prevented alpha-glucosidase aggregation/precipitation and increased protein yield in a modified purification scheme. In fibroblast cells, from adult-onset GSD II patients, D-glucose increased the residual level of alpha-glucosidase activity, suggesting that a structural analogue of d-glucose may be used for enzyme enhancement therapy.

Animals↗
PubMed2004

A general model for genetic regulation of turnover of glycosaminoglycans suggests a possible procedure for prediction of severity and clinical progress of mucopolysaccharidoses.

Mucopolysaccharidoses are rare genetic diseases from the group of lysosomal storage disorders caused by deficiency of enzymes involved in degradation of mucopolysaccharides (glycosaminoglycans, GAGs). Within each mucopolysaccharidosis, there is a continuous spectrum of clinical features from the very severe to the more mildly affected individuals. Surprisingly, in most cases, it is not possible to predict severity and clinical progress (i.e., the natural history) of the disease on the basis of detection of particular mutations or residual activity of the deficient enzyme. In this article, the reasons for such an unexpected difficulty are discussed. A model for the correlation between residual activity of a lysosomal enzyme and the turnover rate of its substrate(s) has been proposed previously by others, however, in that model it was assumed that substrate concentration in the lysosome is not regulated, thus the residual activity of a hydrolase would be the only determinant of the rate of substrate accumulation. On the other hand, both a general model for genetic regulation of turnover of GAGs and results of very recent studies strongly suggest that expression of genes coding for enzymes involved in GAG synthesis is precisely regulated and may vary between individuals. Therefore, we propose that apart from measurement of residual activity of the enzyme involved in degradation of GAGs, the efficiency of synthesis of these compounds should also be estimated. If the hypothesis presented in this article is true, the ratio of the synthesis of glycosaminoglycans to the residual activity of the deficient enzyme should be of considerable prognostic value.

Gene Expression Regulation↗
PubMedDate not supplied

Mucopolysaccharidosis I: a comparative study of haplotypes Eco47III-NspI sites frequencies in patients and healthy subjects of Mexican population.

BACKGROUND: Mucopolysaccharidosis I (MPS-I) is an autosomal recessive disorder, which is caused by mutations in the IDUA gene. It induces the deficiency of glycosidase alpha-L-duronidase. The enzyme that is required for the degradation of heparan and dermatan sulfate. This disorder expresses a wide range of clinical symptoms (severe mental retardation, skeletal deformations, hepatosplenomegaly, corneal clouding and mild visceral organ involvement). In the present paper, we report the frequencies of haplotypes of the Eco47III-NspI sites, in the IDUA gene, in Mexican healthy and in MPS-I individuals. METHODS: Eco47III and NspI intragenic polymorphisms in IDUA gene were studied in 262 (524 chromosomes) Mexican healthy subjects and in 53 (106 chromosomes) MPS-I patients. RESULTS: The genotypes for IDUA Eco47III and NspI sites in Mexicans were in agreement with Hardy-Weinberg expectations. Allele frequency distributions for individual sites differed (P < 0.05) in both groups. Haplotype Eco47III-NspI frequencies of Mexican MPS-I patients also differed from those of the normal Mexican population. The data provide evidence of linkage disequilibrium, since the MPS-I group constitutes a subset of the Mexican control population. The disequilibrium in Mexican MPS-I patients was defined by an increase in the haplotype A1B2, and deficiency in A2B1, with respect to normal population (P < 0.05). CONCLUSIONS: Our results support that these polymorphisms can be associated to mutations in IDUA gene, which leads to MPS-I in Mexican patients. On the other hand, these polymorphisms can be used to identify heterozygosity when they are informative.

Adult↗
PubMed1982

Synthesis of L-idaro-1,4-lactone, an inhibitor of alpha-L-idosiduronase.

L-idaro-1,4-lactone was synthesized by two different, published methods: (1) epimerization of monopotassium D-glucarate by refluxing in aqueous barium hydroxide, and (2) oxidation of L-iditol by heating in dilute nitric acid. The lactone, formed by heat dehydration from aqueous solution at low pH, was purified by paper chromatography, and quantitated by gas-liquid chromatography using inositol as the internal standard. The monolactone inhibited human, seminal-fluid alpha-L-idosiduronase activity, with either phenyl or 4-methylumbelliferyl alpha-L-idosiduronic acid as the substrate, to the same degree as D-glucaro-1,4-lactone inhibits alpha-D-glucosiduronase.

Glucaric Acid↗
PubMed1983

Improved concanavalin A-Sepharose elution by specific readsorption of glycoproteins.

Elution of bound glycoproteins from concanavalin A-Sepharose can be made more efficient by their readsorption to a Blue A agarose column (specific) and Green A agarose column (less-specific) during recycling of the elution buffer. Three lysosomal enzymes were eluted in this way with marked improvement in their specific activities, time and handling and amount of eluting ligand used.

Adsorption↗
PubMed2003

The activities of some glycosaminoglycan-degrading enzymes in uterine leiomyomas.

The activities of some glycosaminoglycan-degrading enzymes in uterine leiomyomas. Both normal human myometrium and uterine leiomyoma contain several glycosaminoglycans (GAGs). In contrast to many normal and tumour tissues the amount of hyaluronic acid (HA) is very low and the proportional amount of sulphated glycosaminoglycans is distinctly higher. We compared the activity of GAG-degrading enzymes in normal myometrium and in uterine leiomyomas. Growth of uterine leiomyomas results in significant reduction in the activities of neutral endoglycosidases degrading most of the sulphated glycosaminoglycans. The activities of acid endoglycosidases also decreased (with the exception of chondroitin-6-sulphate). Thus, the differentiated activity of glycosidases degrading glycosaminoglycans can be a factor modifying the quantity of GAGs.

Adult↗
PubMed1984

Sequence variation in heparin octasaccharides with high affinity for antithrombin III.

We have isolated from nitrous acid cleavage products of heparin two major octasaccharide fragments which bind with high affinity to human antithrombin. Octasaccharide S, with the predominant structure iduronic acid----N-acetylglucosamine 6-O-sulfate----glucuronic acid-----N-sulfated glucosamine 3,6-di-O-sulfate----iduronic acid 2-O-sulfate----N-sulfated glucosamine 6-O-sulfate----iduronic acid 2-O-sulfate----anhydromannitol 6-O-sulfate, is sensitive to cleavage by Flavobacterium heparinase as well as platelet heparitinase and binds to antithrombin with a dissociation constant of (5-15) X 10(-8) M. Octasaccharide R, with the predominant structure iduronic acid 2-O-sulfate----N-sulfated glucosamine 6-O-sulfate----iduronic acid----N-acetylglucosamine 6-O-sulfate----glucuronic acid----N-sulfated glucosamine 3,6-di-O-sulfate----iduronic acid 2-O-sulfate----anhydromannitol 6-O-sulfate, is resistant to degradation by both enzymes and binds antithrombin with a dissociation constant of (4-18) X 10(-7) M. The occurrence of a 15-17% replacement of N-sulfated glucosamine 3,6-di-O-sulfate with N-sulfated glucosamine 3-O-sulfate and a 10-12% replacement of iduronic acid with glucuronic acid in both octasaccharides indicates that these substitutions have little or no effect on the binding of the oligosaccharides to the protease inhibitor. When bound to antithrombin, both octasaccharides produce a 40% enhancement in the intrinsic fluorescence of the protease inhibitor and a rate of human factor Xa inhibition of 5 X 10(5) M-1 s-1 as monitored by stopped-flow fluorometry. This suggests that the conformation of antithrombin in the region of the factor Xa binding site is similar when the protease inhibitor is complexed with either octasaccharide.

Acetylglucosaminidase↗