Chemical chaperones improve transport and enhance stability of mutant α-glucosidases in glycogen storage disease type II

Okumiya, Toshika; Kroos, Marian A.; Vliet, Laura Van de; Takeuchi, Hiroaki; Ploeg, Ans T. van der; Reuser, Arnold

doi:10.1016/j.ymgme.2006.09.010

Cited by 93 publications

(81 citation statements)

References 50 publications

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“…This therapy is based on the concept that imino sugars including DNJ and NB-DNJ interact with mutant GAA proteins, and thereby improve their stability and transportation to lysosomes. 13,14,28 However, these imino sugars are potent inhibitors of a-glucosidases including GAA and intestinal maltase-glucoamylase, and the administration of an excess dose results in intracellular storage of glycogen, 29 and glucosylated and galactosylated oligosaccharides. 30 So, it seems to be difficult to determine the proper doses of these chemicals for pharmacological chaperone therapy, and inadequate doses of them would worsen Pompe disease and might lead to diarrhea.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the mutant GAA species for which imino sugars are effective are limited. 13,14,28 Hence, characterization of mutant GAAs responsive to imino sugars, and detailed information about the complex formation of a mutant GAA and an imino sugar are strongly required for improvement of pharmacological chaperone therapy.…”

Section: Discussionmentioning

confidence: 99%

“…12 As such, potential pharmacological chaperones for GAA, imino sugars including 1-deoxynojirimycin (DNJ) and N-butyl-deoxynojirimycin (NB-DNJ) are known. 13,14 However, mutant GAAs responsive to these imino sugars are restricted to a limited group with specific amino acid substitutions, and the enhancing effects of the imino sugars available are not so strong. [13][14][15] For further improvement of pharmacological chaperone therapy for Pompe disease, detailed information on mutant GAAs responsive to small molecules is required.…”

Section: Introductionmentioning

confidence: 99%

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Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones

et al. 2011

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“…Other groups have utilized methods such as double immunocytochemistry to show proper cellular localization of mutant proteins. Okumiya et al showed proper lysosomal localization of mutated alpha-glucosidase by double immunocytochemistry for alpha-glucosidase and wild-type beta-hexoseaminidase, a lysosomal protein [76]. For plasma membrane proteins, proper localization can be assessed simply by confocal microscopy or flow cytometry [77].…”

Section: Experimental End Points For Demonstrating Chaperone Activitymentioning

confidence: 99%

“…These studies are based upon known differences between immature and mature processed proteins, which in many cases involve differences in the molecular weights of immature and mature proteins. For instance, since the immature, intermediate, and mature alpha-glucosidase are 110, 95, and 76 kD in size, respectively, Okiyuma et al assayed by immunoblotting for increased levels of 76 kD alpha glucosidase after treatment with the test compound [76]. Some investigators also employ pulse chase studies to monitor protein maturation [78].…”

Section: Experimental End Points For Demonstrating Chaperone Activitymentioning

confidence: 99%

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

Sauer

Patel

Chan

et al. 2008

Expert Review of Ophthalmology

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SUMMARYRecent studies suggest that pathological processes involved in age-related macular degeneration (AMD) might induce endoplasmic reticulum (ER) stress. Growing evidence demonstrates the ability of chemical chaperones to decrease ER stress and ameliorate ER stress-related disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for AMD. In this review, we examine the evidence suggesting a role for ER stress in AMD. Furthermore, we discuss the use of chaperone therapy for the treatment of ER stress-associated diseases, including other neurodegenerative diseases and retinopathies. Finally, we examine strategies for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human disease.

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Competitive and Covalent Inhibitors of Human Lysosomal Retaining Exoglucosidases

Breen

Artola

et al. 2018

Encyclopedia of Life Sciences

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Deficiency in human acid glucosylceramidase (GBA1, a retaining β‐glucosidase) causes the lysosomal sphingolipid storage disorder Gaucher disease, whereas deficiency in human acid α‐glucosidase (GAA, a retaining α‐glucosidase) triggers the lysosomal glycogen storage disorder Pompe disease. Both enzymes process their substrate following a two‐step double‐displacement mechanism involving a covalent enzyme–substrate intermediate. Structural analysis of glycosidases complexed to substrates and inhibitors has provided insight into the reaction coordinates followed by glycosidases during catalytic hydrolysis and has assisted in the design of potent and selective inhibitors. Competitive and covalent inhibitors of both GBA1 and GAA have been developed in the past decades, for fundamental studies, as diagnostics tools, leads for drug development and therapeutic drugs for the clinical treatment of lysosomal storage diseases. Key Concepts The structural and functional diversity of glycoconjugates is reflected by the vast number of glycoprocessing enzymes encountered in all domains of life. Retaining glycosidases form a covalent intermediate during substrate processing, whereas inverting glycosidases do not. Competitive and covalent retaining glycosidase inhibitors exist, whereas inverting glycosidases can normally only be blocked by competitive inhibitors. Both covalent and competitive glycosidase inhibitors are found in nature and serve as inspiration for the design of synthetic inhibitors. Structural analysis of glycosidases complexed to substrates and inhibitors provides insight into the reaction coordinates followed by glycosidases during the catalytic cycle. Conformational analysis of the reaction coordinate of glycosidases is key in the design of potent and selective inhibitors. Glycosidase inhibitors may serve as leads for drug development. Activity‐based glycosidase probes can be applied in the discovery of glycosidase activities. Activity‐based probes are useful starting points for the development of diagnostics assays in disease areas in which glycosidase activities are involved. Genetic deficiency in glycosidases is the basis of numerous inherited disorders including Gaucher disease and Pompe disease.

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Chemical chaperones improve transport and enhance stability of mutant α-glucosidases in glycogen storage disease type II

Cited by 93 publications

References 50 publications

Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones

Biochemical and structural study on a S529V mutant acid α-glucosidase responsive to pharmacological chaperones

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

Competitive and Covalent Inhibitors of Human Lysosomal Retaining Exoglucosidases

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