Target Validation Information
Target ID T84173
Target Name Glucosylceramidase
Target Type
Successful
Drug Potency against Target N-(Propylamide-benzophenone)-1-deoxynojirimycin Drug Info IC50 = 350 nM [530532]
(2R,3S,4S,5R)-2-propylpiperidine-3,4,5-triol Drug Info IC50 = 560 nM [530788]
(2R,3S,4S,5R)-2-nonylpiperidine-3,4,5-triol Drug Info Ki = 2.2 nM [530788]
N-(Propylamide-acetophenone)-1-deoxynojirimycin Drug Info IC50 = 1650 nM [530532]
(2R,3S,4S,5R)-2-hexylpiperidine-3,4,5-triol Drug Info IC50 = 19 nM [530788]
L-Isofagomine Drug Info IC50 = 9000 nM [529573]
1,5-Dideoxy-1,5-imino-D-xylitol Drug Info IC50 = 2300 nM [529573]
Action against Disease Model Isofagomine tartrate Isofagomine tartrate increases L444P GCase activity in Gaucher patient-derived cells [553019] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations beta-Glucosidase 2 (GBA2) is a resident enzyme of the endoplasmic reticul uM thought to play a role in the metabolism of bile acid-glucose conjugates. To gain insight into the biological function of this enzyme and its substrates, we generated mice deficient in GBA2 and found that these animals had normal bile acid metabolism. Knockout males exhibited impaired fertility. Microscopic examination of sperm revealed large round heads (globozoospermia), abnormal acrosomes, and defective mobility. Glycolipids, identified as glucosylceramides by mass spectrometry, acc uMulated in the testes, brains, and livers of the knockout mice but did not cause obvious neurological symptoms, organomegaly, or a reduction in lifespan. Recombinant GBA2 hydrolyzed glucosylceramide to glucose and ceramide; the same reaction catalyzed by the beta-glucosidase acid 1 (GBA1) defective in subjects with the Gaucher's form of lysosomal storage disease. [530532]
References
Ref 530532Bioorg Med Chem. 2010 Jan 1;18(1):267-73. Epub 2009 Oct 31.Nanomolar affinity, iminosugar-based chemical probes for specific labeling of lysosomal glucocerebrosidase.
Ref 530788Bioorg Med Chem. 2010 Apr 1;18(7):2645-50. Epub 2010 Feb 20.Synthesis of new beta-1-C-alkylated imino-L-iditols: A comparative study of their activity as beta-glucocerebrosidase inhibitors.
Ref 530788Bioorg Med Chem. 2010 Apr 1;18(7):2645-50. Epub 2010 Feb 20.Synthesis of new beta-1-C-alkylated imino-L-iditols: A comparative study of their activity as beta-glucocerebrosidase inhibitors.
Ref 530532Bioorg Med Chem. 2010 Jan 1;18(1):267-73. Epub 2009 Oct 31.Nanomolar affinity, iminosugar-based chemical probes for specific labeling of lysosomal glucocerebrosidase.
Ref 530788Bioorg Med Chem. 2010 Apr 1;18(7):2645-50. Epub 2010 Feb 20.Synthesis of new beta-1-C-alkylated imino-L-iditols: A comparative study of their activity as beta-glucocerebrosidase inhibitors.
Ref 529573Bioorg Med Chem. 2008 Aug 1;16(15):7330-6. Epub 2008 Jun 18.In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures.
Ref 529573Bioorg Med Chem. 2008 Aug 1;16(15):7330-6. Epub 2008 Jun 18.In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures.
Ref 553019The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of beta-glucosidase. FEBS J. 2010 Apr;277(7):1618-38. doi: 10.1111/j.1742-4658.2010.07588.x. Epub 2010 Feb 10.

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