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

Steet, Richard; Chung, Sungwon; Lee, Wang-Sik; Pine, C.W.; Do, Hung; Kornfeld, Stuart

doi:10.1016/j.bcp.2006.12.015

Cited by 50 publications

(28 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is based on the observation that binding of competitive inhibitors can stabilize both normal and N370S GCase against thermal denaturation and in cell culture lead to an increase in lysosomal levels of the enzymes. This has resulted in the development of several competitive inhibitors as "chemical chaperones" with the goal of promoting folding of the mutant protein in the ER and facilitating transport to the lysosome where, under lysosomal pH conditions, the inhibitor dissociates and the enzyme regains activity (17,18,(21)(22)(23).…”

mentioning

confidence: 99%

X-ray and Biochemical Analysis of N370S Mutant Human Acid β-Glucosidase

Wei¹,

Hughes²,

Boucher³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Gaucher disease is caused by mutations in the enzyme acid ␤-glucosidase (GCase), the most common of which is the substitution of serine for asparagine at residue 370 (N370S). To characterize the nature of this mutation, we expressed human N370S GCase in insect cells and compared the x-ray structure and biochemical properties of the purified protein with that of the recombinant human GCase (imiglucerase, Cerezyme). The x-ray structure of N370S mutant acid ␤-glucosidase at acidic and neutral pH values indicates that the overall folding of the N370S mutant is identical to that of recombinant GCase. Subtle differences were observed in the conformation of a flexible loop at the active site and in the hydrogen bonding ability of aromatic residues on this loop with residue 370 and the catalytic residues Glu-235 and Glu-340. Circular dichroism spectroscopy showed a pH-dependent change in the environment of tryptophan residues in imiglucerase that is absent in N370S GCase. The mutant protein was catalytically deficient with reduced V max and increased K m values for the substrate p-nitrophenyl-␤-D-glucopyranoside and reduced sensitivity to competitive inhibitors. N370S GCase was more stable to thermal denaturation and had an increased lysosomal half-life compared with imiglucerase following uptake into macrophages. The competitive inhibitor N-(n-nonyl)deoxynojirimycin increased lysosomal levels of both N370S and imiglucerase 2-3-fold by reducing lysosomal degradation. Overall, these data indicate that the N370S mutation results in a normally folded but less flexible protein with reduced catalytic activity compared with imiglucerase.

show abstract

mentioning

confidence: 99%

X-ray and Biochemical Analysis of N370S Mutant Human Acid β-Glucosidase

Wei¹,

Hughes²,

Boucher³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…[53] It also facilitates trafficking of the enzyme to the lysosomes and have the potential to attenuate the unfolded protein response and prevent ER stress that can lead to apoptosis and inflammatory response. [54] This approach is especially applicable in GD because only a modest increase in residual GC should be sufficient to ameliorate the phenotype.…”

Section: Pharmacological Chaperon Therapy (Pct)mentioning

confidence: 99%

“…This iminosugar can bind, stabilize and promote lysosomal trafficking and increase activity of N370S mutant form of the enzyme GC in cultured fibroblasts in vivo as well as in mice for GCase mutations: V394L, D409H, or D409V. [53,56] IFG can also increase the lysosomal activity of L444p mutant form of GC enzyme in cells and tissues. IFG has also a broad tissue distribution including access to the CNS and multiple tissues thus merit therapeutic option for patients with neuropathic and non-neuropathic GD.…”

Section: Isofagamine (Ifg) the Pharmacological Chaperon Iminosugar Ismentioning

confidence: 99%

Overview of Gaucher Disease and Its Management

Katakam¹

2017

WJPR

View full text Add to dashboard Cite

Gaucher disease (GD) is an inherited, rare, lysosomal storage disorder caused by a genetic deficiency of glucocerebrosidase. enzyme replacement therapy has been the mainstay of treatment with its major disadvantage of long life dependency on biweekly IV therapy. It was more than a decade later when the substrate reduction therapy -an oral treatment -was approved for Gaucher disease. Future therapeutic modalities will include pharmacological chaperon and possibly gene therapy. The aim of this review is to high light the gaucher disease and its management.

show abstract

“…Isofagomine was identifi ed as a lead structure based on its ability to increase GBA activity more than 2-fold in N370S-derived cell lines ( 62,63 ). Importantly, isofagomine stabilizes recombinant GBA as measured by differential scanning fl uorimetry ( 64 ).…”

Section: Isofagominementioning

confidence: 99%