Yoshimizu, M., Tajima, Y., Matsuzawa, F., Aikawa, S., Iwamoto, K., Kobayashi, T. et al. Binding parameters and thermodynamics of the interaction of imino sugars with a recombinant human acid α-glucosidase (alglucosidase alfa): Insight into the complex formation mechanism. Clin. Chim. Acta. 391, 68-73
Department of Clinical Genetics, The Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan. Clinica Chimica Acta
(Impact Factor: 2.82).
06/2008; 391(1-2):68-73. DOI: 10.1016/j.cca.2008.02.014
Recently, enzyme enhancement therapy (EET) for Pompe disease involving imino sugars, which act as potential inhibitors of acid alpha-glucosidases in vitro, to improve the stability and/or transportation of mutant acid alpha-glucosidases in cells was studied and attracted interest. However, the mechanism underlying the molecular interaction between the imino sugars and the enzyme has not been clarified yet.
We examined the inhibitory and binding effects of four imino sugars on a recombinant human acid alpha-glucosidase, alglucosidase alfa, by means of inhibition assaying and isothermal titration calorimetry (ITC). Furthermore, we built structural models of complexes of the catalytic domain of the enzyme with the imino sugars bound to its active site by homology modeling, and examined the molecular interaction between them.
All of the imino sugars examined exhibited a competitive inhibitory action against the enzyme, 1-deoxynojirimycin (DNJ) exhibiting the strongest action among them. ITC revealed that one compound molecule binds to one enzyme molecule and that DNJ most strongly binds to the enzyme among them. Structural analysis revealed that the active site of the enzyme is almost completely occupied by DNJ.
These biochemical and structural analyses increased our understanding of the molecular interaction between a human acid alpha-glucosidase and imino sugars.
Available from: Mats I Nilsson
- "Lastly, the dosages necessary to attenuate GSDII disease progression are up to 100-fold greater compared to those in other lysosomal storage disorders , underscoring the importance of developing adjunctive therapies that augment enzyme delivery/uptake. Although several experimental treatments have shown promise including gene therapy   , chaperone therapy , substrate reduction therapy , hematopoietic cell therapy , biochemical modification of GAA  , β 2 -agonist supplementation  , and physical activity/nutritional intervention       , many of these alternative approaches are still in the early developmental stages. Our group has previously demonstrated that exercise has remarkable therapeutic potency with ubiquitous effects on multiple organ systems  that may be difficult, if not impossible, to replicate with artificial means . "
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ABSTRACT: BACKGROUND: Aerobic exercise may be used in conjunction with enzyme replacement therapy (ERT) to attenuate cardiovascular deconditioning, skeletal muscle wasting, and loss of motor function in Pompe disease (glycogen storage disease type II; GSDII), but the effects on lysosomal glycogen content and macroautophagy have not been defined to date. PURPOSE: The main objectives of this study were to determine if acute aerobic exercise enhances 24-h uptake of recombinant human enzyme (rhGAA; Myozyme® [aim 1]) and if endurance training improves disease pathology when combined with ERT [aim 2] in Pompe mice. METHODS: For the first aim in our study, Pompe mutant mice (6(neo)/6(neo)) were grouped into ERT (Myozyme® injection only [40mg/kg]) and ERT+EX (Myozyme® injection followed by 90min treadmill exercise) cohorts, and enzyme uptake was assessed in the heart and quadriceps 24h post injection. For the second aim of our study, mutant mice were randomized into control, endurance-trained, enzyme-treated, or combination therapy groups. Exercised animals underwent 14weeks of progressive treadmill training with or without biweekly Myozyme® injections (40mg/kg) and tissues were harvested 1week post last treatment. RESULTS: Myozyme® uptake (GAA activity) was not improved in ERT+EX over ERT alone at 24-h post injection. Endurance exercise training, with or without ERT, improved aerobic capacity and normalized grip strength, motor function, and lean mass (P<0.05), but did not reduce glycogen content or normalize macroautophagy beyond traditional enzyme replacement therapy. CONCLUSIONS: Endurance training is beneficial as an adjunctive therapy to ERT in Pompe disease, although it works by mechanisms independent of a reduction in glycogen content.
Available from: Benedikt Schoser
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ABSTRACT: Glycogen storage disease type II (GSDII)/Pompe disease is an autosomal recessive multi-system disorder due to a deficiency of the glycogen-degrading lysosomal enzyme, acid alpha-glucosidase. Without adequate levels of alpha-glucosidase, there is a progressive accumulation of glycogen inside the lysosome, resulting in lysosomal expansion in many tissues, although the major clinical manifestations are seen in cardiac and skeletal muscle. Pompe disease presents as a continuum of clinical phenotypes. In the most severe cases, disease onset occurs in infancy and death results from cardiac and respiratory failure within the first 1 or 2 years of life. In the milder late-onset forms, cardiac muscle is spared and muscle weakness is the primary symptom. Weakness of respiratory muscles is the major cause of mortality in these cases. Enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme; Genzyme Corp., Framingham, MA) is now available for all forms of glycogen storage disease type II. ERT has shown remarkable success in reversing pathology in cardiac muscle and extending life expectancy in infantile patients. However, skeletal muscle has proven to be a more challenging target for ERT. Although ERT is less effective in skeletal muscle than was hoped for, the lessons learned from both clinical and pre-clinical ERT studies have greatly expanded our understanding of the pathogenesis of the disease. A combination of fundamental studies and clinical follow-up, as well as exploration of other therapies, is necessary to take treatment for glycogen storage disease type II to the next level.
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ABSTRACT: A large number of compounds mimicking the structures of monosaccharides or oligosaccharides have been discovered from natural sources. Such sugar mimics inhibit carbohydrate-degrading enzymes because of a structural resemblance to the sugar moiety of the natural substrate. Carbohydrate-degrading enzymes are involved in a wide range of important biological processes, such as intestinal digestion, posttranslational processing of the sugar chain of glycoproteins, their quality control mechanisms, lysosomal catabolism of glycoconjugates, and some viral infections. It has now been realized that inhibitors of the enzymes have enormous therapeutic potential in diabetes and lysosomal storage disorders. In this review, the general bioactivity, current applications, and the prospects for new therapeutic applications are described.
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