Gaucher Disease-Associated Glucocerebrosidases Show Mutation-Dependent Chemical Chaperoning Profiles

Sawkar, Anu R.; Adamski‐Werner, Sara L.; Cheng, Wei‐Chieh; Wong, Chi‐Huey; Beutler, Ernest; Zimmer, Klaus–Peter; Kelly, Jeffery W.

doi:10.1016/j.chembiol.2005.09.007

Cited by 180 publications

(208 citation statements)

References 43 publications

Supporting

Mentioning

191

Contrasting

Unclassified

Order By: Relevance

“…Less than 10% inhibition of the lysosomal hydrolases β-galactosidase, β-N-acetylhexosaminidase, β-mannosidase and β-glucuronidase was observed at 500 μM IFG. The negligible inhibition of these enzymes by IFG is consistent with a previous report [13].…”

Section: Effect Of Ifg On the Activity Of Other Lysosomal Glycosidasessupporting

confidence: 93%

“…While both treatments are effective in improving the hematologic and visceral symptoms in patients with mild, non-neuronopathic forms of the disease, their efficacy may be limited by their inability to cross the blood-brain barrier (ERT) or adverse side effects (SRT). Recent studies have demonstrated the ability of sugar analog inhibitors to increase the activity of mutant lysosomal enzymes in patient fibroblasts by acting as pharmacological chaperones [10][11][12][13][14][15]. As active site inhibitors, these compounds bind to the mutant enzymes and stabilize them in the ER, thereby preventing their ER-associated degradation and facilitating their folding and transport out of this compartment to lysosomes.…”

Section: Discussionmentioning

confidence: 99%

“…Several researchers have demonstrated the ability of iminosugars to increase the activity of mutant forms of GlcCerase [10][11][12][13][14][15]. We have recently reported that the iminosugar, isofagomine (IFG), enhances N370S GlcCerase activity by approximately 3-fold by facilitating its folding and transport out of the ER to lysosomes.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Steet

Chung

Lee

et al. 2007

Biochemical Pharmacology

View full text Add to dashboard Cite

Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-β-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. We recently demonstrated that isofagomine (IFG), an iminosugar that binds to the active site of GlcCerase, enhances the folding, transport and activity of the N370S mutant form of GlcCerase. In this study we compared the effects of IFG on a number of other glucosidases and glucosyltransferases. We report that IFG has little or no inhibitory activity towards intestinal disaccharidase enzymes, ER α-glucosidase II or glucosylceramide synthase at concentrations previously shown to enhance N370S GlcCerase folding and trafficking in Gaucher fibroblasts. Furthermore, treatment of wild type fibroblasts with high doses of IFG did not alter the processing of newly synthesized N-linked oligosaccharides. These findings support further evaluation of IFG as a potential therapeutic agent in the treatment of some forms of Gaucher disease.

show abstract

Section: Effect Of Ifg On the Activity Of Other Lysosomal Glycosidasessupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Steet

Chung

Lee

et al. 2007

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…The use of small molecule chaperones, meanwhile tested in the therapy of some inborn errors of metabolism, are therefore likely to be beneficial also in MSD. 44,45 …”

Section: Cellular Phenotype In Msd Fibroblasts: Impairments Of Endogementioning

confidence: 99%

SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency

et al. 2011

View full text Add to dashboard Cite

Multiple Sulfatase Deficiency (MSD) is caused by mutations in the sulfatase-modifying factor 1 gene encoding the formylglycine-generating enzyme (FGE). FGE post translationally activates all newly synthesized sulfatases by generating the catalytic residue formylglycine. Impaired FGE function leads to reduced sulfatase activities. Patients display combined clinical symptoms of single sulfatase deficiencies. For ten MSD patients, we determined the clinical phenotype, FGE expression, localization and stability, as well as residual FGE and sulfatase activities. A neonatal, very severe clinical phenotype resulted from a combination of two nonsense mutations leading to almost fully abrogated FGE activity, highly unstable FGE protein and nearly undetectable sulfatase activities. A late infantile mild phenotype resulted from FGE G263V leading to unstable protein but high residual FGE activity. Other missense mutations resulted in a late infantile severe phenotype because of unstable protein with low residual FGE activity. Patients with identical mutations displayed comparable clinical phenotypes. These data confirm the hypothesis that the phenotypic outcome in MSD depends on both residual FGE activity as well as protein stability. Predicting the clinical course in case of molecularly characterized mutations seems feasible, which will be helpful for genetic counseling and developing therapeutic strategies aiming at enhancement of FGE.

show abstract

“…The ability of several glucose and galactose analogs to increase the activity of the defective enzymes in Gaucher and Fabry disease cells, respectively, has been recently demonstrated by several groups (15)(16)(17)(18)(19)(20). Although the increased enzyme activity is believed to result from improved folding and trafficking of the mutant enzymes, insight into the actual mechanisms whereby these small molecules exert their action is limited.…”

mentioning

confidence: 99%

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

Steet

Chung

Wustman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

203

233

View full text Add to dashboard Cite

Gaucher disease is a lysosomal storage disorder caused by deficiency in lysosomal acid ␤-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. One of the most prevalent disease-causing mutations, N370S, results in an enzyme with lower catalytic activity and impaired exit from the endoplasmic reticulum. Here, we report that the iminosugar isofagomine (IFG), an active-site inhibitor, increases GlcCerase activity 3.0 ؎ 0.6-fold in N370S fibroblasts by several mechanisms. A major effect of IFG is to facilitate the folding and transport of newly synthesized GlcCerase in the endoplasmic reticulum, thereby increasing the lysosomal pool of the enzyme. In addition, N370S GlcCerase synthesized in the presence of IFG exhibits a shift in pH optimum from 6.4 to 5.2 and altered sensitivity to SDS. Although IFG fully inhibits GlcCerase in the lysosome in an in situ assay, washout of the drug leads to partial recovery of GlcCerase activity within 4 h and full recovery by 24 h. These findings provide support for the possible use of active-site inhibitors in the treatment of some forms of Gaucher disease.

show abstract

Gaucher Disease-Associated Glucocerebrosidases Show Mutation-Dependent Chemical Chaperoning Profiles

Cited by 180 publications

References 43 publications

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

Contact Info

Product

Resources

About