ArticleThe Journal of biological chemistry2013
β-Glucosidase 2 (GBA2) activity and imino sugar pharmacology.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 80 citations in OpenAlex.
- Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review.International journal of molecular sciences · 2020Pooled it
- Assessment of Target Engagement in a First-in-Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders.Clinical and translational science · 2021Trial
- Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects.Orphanet journal of rare diseases · 2017Trial
- Miglustat in Neuronopathic Lysosomal Storage Disorders: Biological Rationale, Clinical Evidence, and Limits of Repurposing.International journal of molecular sciences · 2026Review
- Investigation of Carbonic Anhydrase Inhibition, Antioxidant Properties, and Selective Anticancer Activity of Methyl-Substituted Halogenated and Methoxy Conduritols.BioMed research international · 2026Article
- An injectable hydrogel containingRSC advances · 2025Article
- Lysosomal free sialic acid storage disorder iPSC-derived neural cells display altered glycosphingolipid metabolism.Scientific reports · 2025Article
- Synthesis, function, and therapeutic potential of glycosphingolipids.Frontiers in immunology · 2025Review
- Expanding horizons of iminosugars as broad-spectrum anti-virals: mechanism, efficacy and novel developments.Natural products and bioprospecting · 2024Review
- Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature.Neurogenetics · 2024Review
- Severe neurometabolic phenotype inFrontiers in molecular neuroscience · 2023Article
- Impact of Gba2 on neuronopathic Gaucher's disease and α-synuclein accumulation in medaka (Oryzias latipes).Molecular brain · 2021Article
- Effect of Expression of Human Glucosylceramidase 2 Isoforms on Lipid Profiles in COS-7 Cells.Metabolites · 2020Article
- Sphingolipids and plasma membrane hydrolases in human primary bronchial cells during differentiation and their altered patterns in cystic fibrosis.Glycoconjugate journal · 2020Article
- Mechanistic convergence and shared therapeutic targets in Niemann-Pick disease.Journal of inherited metabolic disease · 2020Article
- TheThe Journal of biological chemistry · 2020Article
- Truncated mutants of beta-glucosidase 2 (GBA2) are localized in the mitochondrial matrix and cause mitochondrial fragmentation.PloS one · 2020Article
- Article
- Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson's disease.Molecular neurodegeneration · 2019Article
- Substrate reduction therapy for inborn errors of metabolism.Emerging topics in life sciences · 2019Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
β-Glucosidase 2 (GBA2) is an enzyme that cleaves the membrane lipid glucosylceramide into glucose and ceramide. The GBA2 gene is mutated in genetic neurological diseases (hereditary spastic paraplegia and cerebellar ataxia). Pharmacologically, GBA2 is reversibly inhibited by alkylated imino sugars that are in clinical use or are being developed for this purpose. We have addressed the ambiguity surrounding one of the defining characteristics of GBA2, which is its sensitivity to inhibition by conduritol B epoxide (CBE). We found that CBE inhibited GBA2, in vitro and in live cells, in a time-dependent fashion, which is typical for mechanism-based enzyme inactivators. Compared with the well characterized impact of CBE on the lysosomal glucosylceramide-degrading enzyme (glucocerebrosidase, GBA), CBE inactivated GBA2 less efficiently, due to a lower affinity for this enzyme (higher KI) and a lower rate of enzyme inactivation (k(inact)). In contrast to CBE, N-butyldeoxygalactonojirimycin exclusively inhibited GBA2. Accordingly, we propose to redefine GBA2 activity as the β-glucosidase that is sensitive to inhibition by N-butyldeoxygalactonojirimycin. Revised as such, GBA2 activity 1) was optimal at pH 5.5-6.0; 2) accounted for a much higher proportion of detergent-independent membrane-associated β-glucosidase activity; 3) was more variable among mouse tissues and neuroblastoma and monocyte cell lines; and 4) was more sensitive to inhibition by N-butyldeoxynojirimycin (miglustat, Zavesca®), in comparison with earlier studies. Our evaluation of GBA2 makes it possible to assess its activity more accurately, which will be helpful in analyzing its physiological roles and involvement in disease and in the pharmacological profiling of monosaccharide mimetics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.