Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOZXG5D)

• DOT Name: Non-lysosomal glucosylceramidase (GBA2)
• Synonyms: NLGase; EC 3.2.1.45; Beta-glucocerebrosidase 2; Beta-glucosidase 2; Bile acid beta-glucosidase GBA2; Bile acid glucosyl transferase GBA2; Cholesterol glucosyltransferase GBA2; EC 2.4.1.-; Cholesteryl-beta-glucosidase GBA2; EC 3.2.1.-; Glucosylceramidase 2; Non-lysosomal cholesterol glycosyltransferase; Non-lysosomal galactosylceramidase; EC 3.2.1.46; Non-lysosomal glycosylceramidase
• Gene Name: GBA2
• Related Disease:
  Neoplasm
  Parkinson disease
  Cerebellar ataxia
  Cystic fibrosis
  Gaucher disease
  Hereditary spastic paraplegia 46
  Huntington disease
  Male infertility
  Nervous system disease
  Spastic ataxia
  Trichohepatoenteric syndrome
  Vascular purpura
  Hereditary spastic paraplegia
  Autosomal recessive cerebellar ataxia with late-onset spasticity
  Glaucoma/ocular hypertension
  Niemann-Pick disease type C
• UniProt ID: GBA2_HUMAN
• EC Number: 2.4.1.-; 3.2.1.-; 3.2.1.45; 3.2.1.46
• Pfam ID: PF04685 ; PF12215
• Sequence:
  MGTQDPGNMGTGVPASEQISCAKEDPQVYCPEETGGTKDVQVTDCKSPEDSRPPKETDCC
  NPEDSGQLMVSYEGKAMGYQVPPFGWRICLAHEFTEKRKPFQANNVSLSNMIKHIGMGLR
  YLQWWYRKTHVEKKTPFIDMINSVPLRQIYGCPLGGIGGGTITRGWRGQFCRWQLNPGMY
  QHRTVIADQFTVCLRREGQTVYQQVLSLERPSVLRSWNWGLCGYFAFYHALYPRAWTVYQ
  LPGQNVTLTCRQITPILPHDYQDSSLPVGVFVWDVENEGDEALDVSIMFSMRNGLGGGDD
  APGGLWNEPFCLERSGETVRGLLLHHPTLPNPYTMAVAARVTAATTVTHITAFDPDSTGQ
  QVWQDLLQDGQLDSPTGQSTPTQKGVGIAGAVCVSSKLRPRGQCRLEFSLAWDMPRIMFG
  AKGQVHYRRYTRFFGQDGDAAPALSHYALCRYAEWEERISAWQSPVLDDRSLPAWYKSAL
  FNELYFLADGGTVWLEVLEDSLPEELGRNMCHLRPTLRDYGRFGYLEGQEYRMYNTYDVH
  FYASFALIMLWPKLELSLQYDMALATLREDLTRRRYLMSGVMAPVKRRNVIPHDIGDPDD
  EPWLRVNAYLIHDTADWKDLNLKFVLQVYRDYYLTGDQNFLKDMWPVCLAVMESEMKFDK
  DHDGLIENGGYADQTYDGWVTTGPSAYCGGLWLAAVAVMVQMAALCGAQDIQDKFSSILS
  RGQEAYERLLWNGRYYNYDSSSRPQSRSVMSDQCAGQWFLKACGLGEGDTEVFPTQHVVR
  ALQTIFELNVQAFAGGAMGAVNGMQPHGVPDKSSVQSDEVWVGVVYGLAATMIQEGLTWE
  GFQTAEGCYRTVWERLGLAFQTPEAYCQQRVFRSLAYMRPLSIWAMQLALQQQQHKKASW
  PKVKQGTGLRTGPMFGPKEAMANLSPE
• Function: Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine). GlcCers are membrane glycosphingolipids that have a wide intracellular distribution. They are the main precursors of more complex glycosphingolipids that play a role in cellular growth, differentiation, adhesion, signaling, cytoskeletal dynamics and membrane properties. Involved in the transglucosylation of cholesterol, transfers glucose from GlcCer to cholesterol, thereby modifying its water solubility and biological properties. Under specific conditions, may catalyze the reverse reaction, transferring glucose from cholesteryl-3-beta-D-glucoside to ceramide (such as N-acylsphing-4-enine) (Probable). May play a role in the metabolism of bile acids. Able to hydrolyze bile acid 3-O-glucosides as well as to produce bile acid-glucose conjugates thanks to a bile acid glucosyl transferase activity. Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the galactosyl transfer between GalCers and cholesterol in vitro with lower activity compared with their activity against GlcCers.
• Tissue Specificity: Widely expressed . Mainly expressed in brain, heart, skeletal muscle, kidney and placenta and expressed at lower levels in liver, spleen, small intestine and lung . Detectable in colon, thymus and peripheral blood leukocytes .
• KEGG Pathway:
  Other glycan degradation (hsa00511)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycosphingolipid catabolism (R-HSA-9840310)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[4]
Gaucher disease	DISTW5JG	Strong	Biomarker	[5]
Hereditary spastic paraplegia 46	DISCANV9	Strong	Autosomal recessive	[6]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[7]
Male infertility	DISY3YZZ	Strong	Biomarker	[3]
Nervous system disease	DISJ7GGT	Strong	Altered Expression	[8]
Spastic ataxia	DISIRRA9	Strong	Biomarker	[7]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[9]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[8]
Hereditary spastic paraplegia	DISGZQV1	moderate	Genetic Variation	[8]
Autosomal recessive cerebellar ataxia with late-onset spasticity	DIS08CCQ	Supportive	Autosomal recessive	[10]
Glaucoma/ocular hypertension	DISLBXBY	Disputed	Biomarker	[11]
Niemann-Pick disease type C	DIS492ZO	Limited	Biomarker	[12]

2 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Non-lysosomal glucosylceramidase (GBA2).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Non-lysosomal glucosylceramidase (GBA2).	[14]

References

• [1] The nonlysosomal -glucosidase GBA2 promotes endoplasmic reticulum stress and impairs tumorigenicity of human melanoma cells.FASEB J. 2013 Feb;27(2):489-98. doi: 10.1096/fj.12-215152. Epub 2012 Oct 16.
• [2] Glucosylsphingosine Promotes -Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease.J Neurosci. 2017 Oct 4;37(40):9617-9631. doi: 10.1523/JNEUROSCI.1525-17.2017. Epub 2017 Aug 28.
• [3] Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46).Biochem Biophys Res Commun. 2015 Sep 11;465(1):35-40. doi: 10.1016/j.bbrc.2015.07.112. Epub 2015 Jul 26.
• [4] Evidence for the Involvement of Lipid Rafts and Plasma Membrane Sphingolipid Hydrolases in Pseudomonas aeruginosa Infection of Cystic Fibrosis Bronchial Epithelial Cells.Mediators Inflamm. 2017;2017:1730245. doi: 10.1155/2017/1730245. Epub 2017 Dec 3.
• [5] Assay of -glucosidase 2 (GBA2) activity using lithocholic acid -3-O-glucoside substrate for cultured fibroblasts and glucosylceramide for brain tissue.Biol Chem. 2019 May 27;400(6):745-752. doi: 10.1515/hsz-2018-0438.
• [6] Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. 2013 Feb 7;92(2):238-44. doi: 10.1016/j.ajhg.2012.11.021. Epub 2013 Jan 17.
• [7] Revealing Clusters of Connected Pathways Through Multisource Data Integration in Huntington's Disease and Spastic Ataxia.IEEE J Biomed Health Inform. 2019 Jan;23(1):26-37. doi: 10.1109/JBHI.2018.2865569. Epub 2018 Aug 30.
• [8] Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations.J Biol Chem. 2019 Mar 15;294(11):3853-3871. doi: 10.1074/jbc.RA118.006311. Epub 2019 Jan 20.
• [9] Beta-glucosidase 1 (GBA1) is a second bile acid -glucosidase in addition to -glucosidase 2 (GBA2). Study in -glucosidase deficient mice and humans.Biochem Biophys Res Commun. 2012 Jun 29;423(2):308-12. doi: 10.1016/j.bbrc.2012.05.117. Epub 2012 May 30.
• [10] Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet. 2013 Feb 7;92(2):245-51. doi: 10.1016/j.ajhg.2012.12.012. Epub 2013 Jan 17.
• [11] Optic Nerve Lipidomics Reveal Impaired Glucosylsphingosine Lipids Pathway in Glaucoma.Invest Ophthalmol Vis Sci. 2019 Apr 1;60(5):1789-1798. doi: 10.1167/iovs.18-25802.
• [12] Cytosolic glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease.Neurobiol Dis. 2019 Jul;127:242-252. doi: 10.1016/j.nbd.2019.03.005. Epub 2019 Mar 12.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.