Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0XMD63)

• DOT Name: Lysosomal acid glucosylceramidase (GBA1)
• Synonyms: Lysosomal acid GCase; EC 3.2.1.45; Acid beta-glucosidase; Alglucerase; Beta-glucocerebrosidase; Beta-GC; Beta-glucosylceramidase 1; Cholesterol glucosyltransferase; SGTase; EC 2.4.1.-; Cholesteryl-beta-glucosidase; EC 3.2.1.-; D-glucosyl-N-acylsphingosine glucohydrolase; Glucosylceramidase beta 1; Imiglucerase; Lysosomal cholesterol glycosyltransferase; Lysosomal galactosylceramidase; EC 3.2.1.46; Lysosomal glycosylceramidase
• Gene Name: GBA1
• Related Disease:
  Gaucher disease
  Gaucher disease perinatal lethal
  Parkinson disease
  Gaucher disease type I
  Gaucher disease type II
  Gaucher disease type III
  Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
  Late-onset Parkinson disease
• UniProt ID: GBA1_HUMAN
• PDB ID: 1OGS ; 1Y7V ; 2F61 ; 2J25 ; 2NSX ; 2NT0 ; 2NT1 ; 2V3D ; 2V3E ; 2V3F ; 2VT0 ; 2WCG ; 2WKL ; 2XWD ; 2XWE ; 3GXD ; 3GXF ; 3GXI ; 3GXM ; 3KE0 ; 3KEH ; 3RIK ; 3RIL ; 5LVX ; 6MOZ ; 6Q1N ; 6Q1P ; 6Q6K ; 6Q6L ; 6Q6N ; 6T13 ; 6TJJ ; 6TJK ; 6TJQ ; 6TN1 ; 6YTP ; 6YTR ; 6YUT ; 6YV3 ; 6Z39 ; 6Z3I ; 7NWV
• EC Number: 2.4.1.-; 3.2.1.-; 3.2.1.45; 3.2.1.46
• Pfam ID: PF02055 ; PF17189
• Sequence:
  MEFSSPSREECPKPLSRVSIMAGSLTGLLLLQAVSWASGARPCIPKSFGYSSVVCVCNAT
  YCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQANHTGTGLLLTLQPEQKFQKVKGF
  GGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYNIIRVPMASCDFSIRTYTYADTPDD
  FQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASPWTSPTWLKTNGAVNGKGSLKGQP
  GDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGLLSGYPFQCLGFTPEHQRDFIA
  RDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVVLTDPEAAKYVHGIAVHWYLDFLAPAK
  ATLGETHRLFPNTMLFASEACVGSKFWEQSVRLGSWDRGMQYSHSIITNLLYHVVGWTDW
  NLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQPMFYHLGHFSKFIPEGSQRVGLVASQK
  NDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDPAVGFLETISPGYSIHTYLWRRQ
• Function: Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1')-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose. Plays a central role in the degradation of complex lipids and the turnover of cellular membranes. Through the production of ceramides, participates in the PKC-activated salvage pathway of ceramide formation. Catalyzes the glucosylation of cholesterol, through a transglucosylation reaction where glucose is transferred from GlcCer to cholesterol. GlcCer containing mono-unsaturated fatty acids (such as beta-D-glucosyl-N-(9Z-octadecenoyl)-sphing-4-enine) are preferred as glucose donors for cholesterol glucosylation when compared with GlcCer containing same chain length of saturated fatty acids (such as beta-D-glucosyl-N-octadecanoyl-sphing-4-enine). Under specific conditions, may alternatively catalyze the reverse reaction, transferring glucose from cholesteryl 3-beta-D-glucoside to ceramide (Probable). Can also hydrolyze cholesteryl 3-beta-D-glucoside producing glucose and cholesterol. Catalyzes the hydrolysis of galactosylceramides/GalCers (such as beta-D-galactosyl-(1<->1')-N-acylsphing-4-enine), as well as the transfer of galactose between GalCers and cholesterol in vitro, but with lower activity than with GlcCers. Contrary to GlcCer and GalCer, xylosylceramide/XylCer (such as beta-D-xyosyl-(1<->1')-N-acylsphing-4-enine) is not a good substrate for hydrolysis, however it is a good xylose donor for transxylosylation activity to form cholesteryl 3-beta-D-xyloside.
• KEGG Pathway:
  Other glycan degradation (hsa00511)
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  Glycosphingolipid catabolism (R-HSA-9840310)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gaucher disease	DISTW5JG	Definitive	Autosomal recessive	[1]
Gaucher disease perinatal lethal	DISKSZ4J	Definitive	Autosomal recessive	[2]
Parkinson disease	DISQVHKL	Definitive	Autosomal dominant	[1]
Gaucher disease type I	DIS87KKY	Strong	Autosomal recessive	[2]
Gaucher disease type II	DISCI8IV	Strong	Autosomal recessive	[2]
Gaucher disease type III	DISJFH8S	Strong	Autosomal recessive	[2]
Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome	DIS1K1WK	Strong	Autosomal recessive	[2]
Late-onset Parkinson disease	DIS9IOUI	Strong	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lysosomal acid glucosylceramidase (GBA1).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[3]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[7]
Afegostat	DMRWSKX	Discontinued in Phase 2	Afegostat decreases the activity of Lysosomal acid glucosylceramidase (GBA1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lysosomal acid glucosylceramidase (GBA1).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[10]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Lysosomal acid glucosylceramidase (GBA1).	[3]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] Benzo(a)pyrene exposure in utero exacerbates Parkinson's Disease (PD)-like -synucleinopathy in A53T human alpha-synuclein transgenic mice. Toxicol Appl Pharmacol. 2021 Sep 15;427:115658. doi: 10.1016/j.taap.2021.115658. Epub 2021 Jul 29.
• [8] Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity. J Med Chem. 2011 Feb 24;54(4):1033-58. doi: 10.1021/jm1008902. Epub 2011 Jan 20.
• [9] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.