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

Tajima, Youichi; Saito, Seiji; Ohno, Kazuki; Tsukimura, Takahiro; Tsujino, Seiichi; Sakuraba, Hitoshi

doi:10.1038/jhg.2011.36

Cited by 13 publications

(12 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A subset of these mutants possess protein folding defects, resulting in the ER retention of functionally competent enzymes whose native-like state and lysosomal localization can be rescued by PCs [3,20,21]. PCs for lysosomal enzymes are commonly active site inhibitors that create new hydrogen bonding networks and/or van der Waals interactions that stabilize protein structure [3,22,23]. Although distinct in their globular regions, lysosomal enzymes share a common active site that contains a (beta/alpha)8 TIM barrel [24–26].…”

Section: Structural Mechanismsmentioning

confidence: 99%

Pharmacological chaperoning: A primer on mechanism and pharmacology

Leidenheimer

Ryder

2014

Pharmacological Research

View full text Add to dashboard Cite

Approximately forty percent of diseases are attributable to protein misfolding, including those for which genetic mutation produces misfolding mutants. Intriguingly, many of these mutants are not terminally misfolded since native-like folding, and subsequent trafficking to functional locations, can be induced by target-specific, small molecules variably termed pharmacological chaperones, pharmacoperones, or pharmacochaperones (PCs). PC targets include enzymes, receptors, transporters, and ion channels, revealing the breadth of proteins that can be engaged by ligand-assisted folding. The purpose of this review is to provide an integrated primer of the diverse mechanisms and pharmacology of PCs. In this regard, we examine the structural mechanisms that underlie PC rescue of misfolding mutants, including the ability of PCs to act as surrogates for defective intramolecular interactions and, at the intermolecular level, overcome oligomerization deficiencies and dominant negative effects, as well as influence the subunit stoichiometry of heteropentameric receptors. Not surprisingly, PC-mediated structural correction of misfolding mutants normalizes interactions with molecular chaperones that participate in protein quality control and forward-trafficking. A variety of small molecules have proven to be efficacious PCs and the advantages and disadvantages of employing orthostatic antagonists, active-site inhibitors, orthostatic agonists, and allosteric modulator PCs is considered. Also examined is the possibility that several therapeutic agents may have unrecognized activity as PCs, and this chaperoning activity may mediate/contribute to therapeutic action and/or account for adverse effects. Lastly, we explore evidence that pharmacological chaperoning exploits intrinsic ligand-assisted folding mechanisms. Given the widespread applicability of PC rescue of mutants associated with protein folding disorders, both in vitro and in vivo, the therapeutic potential of PCs is vast. This is most evident in the treatment of lysosomal storage disorders, cystic fibrosis, and nephrogenic diabetes insipidus, for which proof of principle in humans has been demonstrated.

show abstract

Section: Structural Mechanismsmentioning

confidence: 99%

Pharmacological chaperoning: A primer on mechanism and pharmacology

Leidenheimer

Ryder

2014

Pharmacological Research

View full text Add to dashboard Cite

show abstract

“…According to the GAA structural model, whereas both S529 and S619 are located in the (b/a) 8 -barrel domain, mutations of these residues have distinct effects on GAA conformation (Flanagan et al 2009;Tajima et al 2011). An amino acid substitution of serine with valine at position 529 is suggested to induce a moderate structural change adjacent to the surface of the enzyme far from the active site (Tajima et al 2011). In contrast, amino acid substitution of serine with arginine at fibroblasts were electrophoresed followed by immunoblotting using antibodies against GAA and actin.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, amino acid substitution of serine with arginine at fibroblasts were electrophoresed followed by immunoblotting using antibodies against GAA and actin. The band intensities of 76-kDa GAA and actin were quantified by densitometry and normalized to actin position 619 is suggested to lead to a large conformational change near the active site pocket of GAA (Tajima et al 2011). It thus appears that bortezomib is not effective for GAA mutations that induce large conformational perturbations in the enzyme structure.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical presentation of Pompe disease spans a broad spectrum of severity, ranging from a rapid infantile-onset form to a slow late-onset form. The infantile-onset form displays a near complete loss of GAA activity and is characterized by generalized muscle weakness and severe cardiomyopathy, leading to premature death in the first year of life (van den Hout et al 2003). The lateonset form typically displays some residual GAA activity and manifests as slowly progressive respiratory failure and muscle weakness without cardiac involvement (van der Ploeg and Reuser 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Proteasome Inhibitor Bortezomib Enhances the Activity of Multiple Mutant Forms of Lysosomal α-Glucosidase in Pompe Disease

et al. 2014

View full text Add to dashboard Cite

Pompe disease is an autosomal recessive myopathic disorder caused by the deficiency of lysosomal acid aglucosidase (GAA). Recently, we showed that function of mutant GAA in fibroblasts derived from Pompe disease patient carrying c.546G>T mutation is improved by treatment with proteasome inhibitor bortezomib as well as pharmacological chaperone (PC). However, bortezomib-responsive GAA mutations are not fully characterized. In this study, we showed the effect of bortezomib on different mutants of GAA in patient fibroblasts and transiently expressed HEK293T cells. Bortezomib increased the maturation and residual activity of GAA in patient fibroblasts carrying PC-responsive M519V and PC-unresponsive C647W mutations. Enhanced colocalization of GAA with lysosomal marker LAMP2 was also observed in patient fibroblasts after treatment with bortezomib. When four distinct mutant GAAs, which show different response to PC, were overexpressed in HEK293T cells, bortezomib improved the activity of M519V, S529V, and C647W in them (1.3-5.9-fold). These results indicate that bortezomib enhances the activity of some PC-unresponsive GAA mutants as well as PC-responsive mutants.

show abstract

“…69 Both 1-deoxynojirimycin (DNJ, duvoglustat) and miglustat can increase acid a-glucosidase activity in cells expressing different mutant forms of the enzyme and in animal models, since these iminosugars are 10-to 250-fold more selective for a-glucosidase compared to b-glucosidase. 70,71 In particular, DNJ administration to PD mouse model showed daily important reduction of substrate in heart, diaphragm, gastrocnemius, soleus, and brain. 72 In spite of the positive tolerability results of phase 1 studies, duvoglustat showed severe adverse events in 2 patients during phase 2 clinical trial.…”

Section: Pharmacological Chaperonesmentioning

confidence: 99%

Small Molecules

Ortolano

2016

Journal of Inborn Errors of Metabolism and Screening

View full text Add to dashboard Cite

Lysosomal storage disorders are rare genetic disorders due to deficient lysosomal activity, which leads to progressive accumulation of nonmetabolized substrates. Patient's clinical outcomes have significantly improved since the advent of enzyme replacement therapy, even though this therapeutic approach presents important limitations, such as immune reactions, low bioavailability of recombinant enzymes, and incapability to reach the central nervous system. New strategies based on gene therapy or small molecules have been proposed and tested as an alternative to enzyme replacement therapy or to complement it. Small molecules are orally administrated, no antigenic compound that can diffuse across cell membranes and distribute in steady-state concentrations, also reaching the central nervous system. Substrate reduction therapy, pharmacological chaperones, and stop-codon read-through enhancers are small molecules currently available for the treatment of lysosomal storage disorders. This article describes the characteristics of this class of compounds and the possible strategies to improve their efficiency in future development.

show abstract

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

Cited by 13 publications

References 29 publications

Pharmacological chaperoning: A primer on mechanism and pharmacology

Pharmacological chaperoning: A primer on mechanism and pharmacology

Proteasome Inhibitor Bortezomib Enhances the Activity of Multiple Mutant Forms of Lysosomal α-Glucosidase in Pompe Disease

Small Molecules

Contact Info

Product

Resources

About