ArticleThe Journal of biological chemistry2011
X-ray and biochemical analysis of N370S mutant human acid β-glucosidase.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 65 citations in OpenAlex.
- Targeting lysosomal pH restores mitochondrial quality control in GBA1-mutant Parkinson's disease.Translational neurodegeneration · 2026Article
- Classification of GBA1 variants and their impact on Parkinson's disease: an in silico score analysis.NPJ Parkinson's disease · 2025Article
- Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function.Nature communications · 2025Article
- Review
- Cytotoxic lymphocyte effector function is unaffected in patients with Gaucher disease.Frontiers in immunology · 2025Article
- Gaucher disease protects against tuberculosis.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Mutational Analysis and Genotype Investigation of Less Known Gaucher Mutations through Haplotype Analysis in Iranian Gaucher Patients.International journal of molecular and cellular medicine · 2023Article
- Pre- and post-therapeutic evaluation of liver and spleen in type I and type III Gaucher's disease using diffusion tensor imaging.Abdominal radiology (New York) · 2022Article
- Gaucher disease: Basic and translational science needs for more complete therapy and management.Molecular genetics and metabolism · 2021Review
- A baculoviral system for the production of human β-glucocerebrosidase enables atomic resolution analysis.Acta crystallographica. Section D, Structural biology · 2020Article
- Review
- Combination of acid β-glucosidase mutation and Saposin C deficiency in mice reveals Gba1 mutation dependent and tissue-specific disease phenotype.Scientific reports · 2019Article
- Computational modelling approaches as a potential platform to understand the molecular genetics association between Parkinson's and Gaucher diseases.Metabolic brain disease · 2018Article
- Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses.Journal of lipid research · 2018Article
- Design of a New α-1-Molecules (Basel, Switzerland) · 2018Article
- Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives.Advanced drug delivery reviews · 2017Review
- Stabilization of Glucocerebrosidase by Active Site Occupancy.ACS chemical biology · 2017Article
- ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons.Stem cell reports · 2016Article
- Direct site-specific glycoform identification and quantitative comparison of glycoprotein therapeutics: imiglucerase and velaglucerase alfa.The AAPS journal · 2015Article
- Did α-Synuclein and Glucocerebrosidase Coevolve? Implications for Parkinson's Disease.PloS one · 2015Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gaucher disease is caused by mutations in the enzyme acid β-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 β-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-β-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.
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