Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1B5PU)

• DTT Name: Glucosylceramidase (GBA)
• 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
• Gene Name: GBA
• DTT Type: Successful target; [1]
• BioChemical Class: Glycosylase
• UniProt ID: GLCM_HUMAN
• TTD ID: T84173
• EC Number: EC 3.2.1.45
• Sequence:
  MEFSSPSREECPKPLSRVSIMAGSLTGLLLLQAVSWASGARPCIPKSFGYSSVVCVCNAT
  YCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQANHTGTGLLLTLQPEQKFQKVKGF
  GGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYNIIRVPMASCDFSIRTYTYADTPDD
  FQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASPWTSPTWLKTNGAVNGKGSLKGQP
  GDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGLLSGYPFQCLGFTPEHQRDFIA
  RDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVVLTDPEAAKYVHGIAVHWYLDFLAPAK
  ATLGETHRLFPNTMLFASEACVGSKFWEQSVRLGSWDRGMQYSHSIITNLLYHVVGWTDW
  NLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQPMFYHLGHFSKFIPEGSQRVGLVASQK
  NDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDPAVGFLETISPGYSIHTYLWRRQ
• 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.
• KEGG Pathway:
  Other glycan degradation (hsa00511)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway: Glycosphingolipid metabolism (R-HSA-1660662)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Taliglucerase alfa	DM3PZXN	Metabolic disorder	5C50-5D2Z	Approved	[1]
Velaglucerase alfa	DM4BOAS	Gaucher disease type I		Approved	[2]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Isofagomine tartrate	DM2RS0V	Metabolic disorder	5C50-5D2Z	Phase 2	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Afegostat	DMRWSKX	Gaucher disease	5C56.0Y	Discontinued in Phase 2	[4]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
N-Octyl-beta-valienamine	DM39C47	Gaucher disease	5C56.0Y	Preclinical	[5]
NCGC607	DMXG0O1	Gaucher disease	5C56.0Y	Preclinical	[6]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2R,3S,4S,5R)-2-hexylpiperidine-3,4,5-triol	DMDS8AN	Discovery agent	N.A.	Investigative	[7]
(2R,3S,4S,5R)-2-nonylpiperidine-3,4,5-triol	DMIQNX9	Discovery agent	N.A.	Investigative	[7]
(2R,3S,4S,5R)-2-propylpiperidine-3,4,5-triol	DM7GI94	Discovery agent	N.A.	Investigative	[7]
1,5-Dideoxy-1,5-imino-D-xylitol	DMZU1GD	Discovery agent	N.A.	Investigative	[8]
2-(Acetylamino)-2-Deoxy-a-D-Glucopyranose	DMOUG6Y	Discovery agent	N.A.	Investigative	[9]
L-Isofagomine	DM6RKOC	Discovery agent	N.A.	Investigative	[8]
N-(Propylamide-acetophenone)-1-deoxynojirimycin	DMXI4V8	Discovery agent	N.A.	Investigative	[10]
N-(Propylamide-benzophenone)-1-deoxynojirimycin	DMCZHBI	Discovery agent	N.A.	Investigative	[10]

References

• [1] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [2] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [3] 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.
• [4] Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019 Dec;18(12):923-948.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [10] Nanomolar affinity, iminosugar-based chemical probes for specific labeling of lysosomal glucocerebrosidase. Bioorg Med Chem. 2010 Jan 1;18(1):267-73.