Target Information
| Target General Information | Top | |||||
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| Target ID |
T84173
(Former ID: TTDC00014)
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| Target Name |
Glucosylceramidase (GBA)
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| Synonyms |
SGTase; Lysosomal acid glucosylceramidase; Lysosomal acid GCase; Imiglucerase; GLUC; GC; D-glucosyl-N-acylsphingosine glucohydrolase; Cholesteryl-beta-glucosidase; Cholesterol glucosyltransferase; Beta-glucocerebrosidase; Beta-GC; Alglucerase; Acid beta-glucosidase
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| Gene Name |
GBA
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Metabolic disorder [ICD-11: 5C50-5D2Z] | |||||
| Function |
Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramide/GlcCer into free ceramide and glucose. Thereby, plays a central role in the degradation of complex lipids and the turnover of cellular membranes. Through the production of ceramides, participates to the PKC-activated salvage pathway of ceramide formation. Also plays a role in cholesterol metabolism. May either catalyze the glucosylation of cholesterol, through a transglucosylation reaction that transfers glucose from glucosylceramide to cholesterol. The short chain saturated C8:0-GlcCer and the mono-unsaturated C18:0-GlcCer being the most effective glucose donors for that transglucosylation reaction. Under specific conditions, may alternatively catalyze the reverse reaction, transferring glucose from cholesteryl-beta-D-glucoside to ceramide. Finally, may also hydrolyze cholesteryl-beta-D-glucoside to produce D-glucose and cholesterol.
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| BioChemical Class |
Glycosylase
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| UniProt ID | ||||||
| EC Number |
EC 3.2.1.45
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| Sequence |
MEFSSPSREECPKPLSRVSIMAGSLTGLLLLQAVSWASGARPCIPKSFGYSSVVCVCNAT
YCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQANHTGTGLLLTLQPEQKFQKVKGF GGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYNIIRVPMASCDFSIRTYTYADTPDD FQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASPWTSPTWLKTNGAVNGKGSLKGQP GDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGLLSGYPFQCLGFTPEHQRDFIA RDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVVLTDPEAAKYVHGIAVHWYLDFLAPAK ATLGETHRLFPNTMLFASEACVGSKFWEQSVRLGSWDRGMQYSHSIITNLLYHVVGWTDW NLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQPMFYHLGHFSKFIPEGSQRVGLVASQK NDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDPAVGFLETISPGYSIHTYLWRRQ Click to Show/Hide
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| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
| 1 | Taliglucerase alfa | Drug Info | Approved | Metabolic disorder | [1], [2] | |
| 2 | Velaglucerase alfa | Drug Info | Approved | Metabolic disorder | [3], [4] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | Isofagomine tartrate | Drug Info | Phase 2 | Metabolic disorder | [5], [6] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Afegostat | Drug Info | Discontinued in Phase 2 | Gaucher disease | [7] | |
| Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
| 1 | N-Octyl-beta-valienamine | Drug Info | Preclinical | Gaucher disease | [7] | |
| 2 | NCGC607 | Drug Info | Preclinical | Gaucher disease | [8] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 2 Modulator drugs | + | ||||
| 1 | Taliglucerase alfa | Drug Info | [1] | |||
| 2 | Velaglucerase alfa | Drug Info | [4] | |||
| Inhibitor | [+] 12 Inhibitor drugs | + | ||||
| 1 | Isofagomine tartrate | Drug Info | [9], [10] | |||
| 2 | Afegostat | Drug Info | [7] | |||
| 3 | N-Octyl-beta-valienamine | Drug Info | [11] | |||
| 4 | NCGC607 | Drug Info | [8] | |||
| 5 | (2R,3S,4S,5R)-2-hexylpiperidine-3,4,5-triol | Drug Info | [12] | |||
| 6 | (2R,3S,4S,5R)-2-nonylpiperidine-3,4,5-triol | Drug Info | [12] | |||
| 7 | (2R,3S,4S,5R)-2-propylpiperidine-3,4,5-triol | Drug Info | [12] | |||
| 8 | 1,5-Dideoxy-1,5-imino-D-xylitol | Drug Info | [13] | |||
| 9 | 2-(Acetylamino)-2-Deoxy-a-D-Glucopyranose | Drug Info | [14] | |||
| 10 | L-Isofagomine | Drug Info | [13] | |||
| 11 | N-(Propylamide-acetophenone)-1-deoxynojirimycin | Drug Info | [15] | |||
| 12 | N-(Propylamide-benzophenone)-1-deoxynojirimycin | Drug Info | [15] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 4 KEGG Pathways | + | ||||
| 1 | Other glycan degradation | |||||
| 2 | Sphingolipid metabolism | |||||
| 3 | Metabolic pathways | |||||
| 4 | Lysosome | |||||
| Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
| 1 | Sphingolipid Metabolism | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Glycosphingolipid metabolism | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Sphingolipid metabolism | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Nat Rev Drug Discov. 2013 Feb;12(2):87-90. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7444). | |||||
| REF 3 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7464). | |||||
| REF 4 | Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5. | |||||
| REF 5 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7410). | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800023168) | |||||
| REF 7 | Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019 Dec;18(12):923-948. | |||||
| REF 8 | A New Glucocerebrosidase Chaperone Reduces alpha-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism. J Neurosci. 2016 Jul 13;36(28):7441-52. | |||||
| REF 9 | Identification of pharmacological chaperones for Gaucher disease and characterization of their effects on beta-glucocerebrosidase by hydrogen/deuterium exchange mass spectrometry. Chembiochem. 2008 Nov 3;9(16):2650-62. | |||||
| REF 10 | Isofagomine induced stabilization of glucocerebrosidase. Chembiochem. 2008 Nov 3;9(16):2643-9. | |||||
| REF 11 | Chemical modification of the beta-glucocerebrosidase inhibitor N-octyl-beta-valienamine: synthesis and biological evaluation of 4-epimeric and 4-O-(beta-D-galactopyranosyl) derivatives. Bioorg Med Chem. 2002 Jun;10(6):1967-72. | |||||
| REF 12 | Synthesis of new beta-1-C-alkylated imino-L-iditols: A comparative study of their activity as beta-glucocerebrosidase inhibitors. Bioorg Med Chem. 2010 Apr 1;18(7):2645-50. | |||||
| REF 13 | In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures. Bioorg Med Chem. 2008 Aug 1;16(15):7330-6. | |||||
| REF 14 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 15 | Nanomolar affinity, iminosugar-based chemical probes for specific labeling of lysosomal glucocerebrosidase. Bioorg Med Chem. 2010 Jan 1;18(1):267-73. | |||||
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