Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR2MWS4)

• DOT Name: Aspartoacylase (ASPA)
• Synonyms: EC 3.5.1.15; Aminoacylase-2; ACY-2
• Gene Name: ASPA
• Related Disease:
  Canavan disease
  Mild Canavan disease
  Severe Canavan disease
• UniProt ID: ACY2_HUMAN
• PDB ID: 2I3C; 2O4H; 2O53; 2Q51; 4MRI; 4MXU; 4NFR; 4TNU
• EC Number: 3.5.1.15
• Pfam ID: PF04952
• Sequence:
  MTSCHIAEEHIQKVAIFGGTHGNELTGVFLVKHWLENGAEIQRTGLEVKPFITNPRAVKK
  CTRYIDCDLNRIFDLENLGKKMSEDLPYEVRRAQEINHLFGPKDSEDSYDIIFDLHNTTS
  NMGCTLILEDSRNNFLIQMFHYIKTSLAPLPCYVYLIEHPSLKYATTRSIAKYPVGIEVG
  PQPQGVLRADILDQMRKMIKHALDFIHHFNEGKEFPPCAIEVYKIIEKVDYPRDENGEIA
  AIIHPNLQDQDWKPLHPGDPMFLTLDGKTIPLGGDCTVYPVFVNEAAYYEKKEAFAKTTK
  LTLNAKSIRCCLH
• Function: Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it acts as a scavenger of NAA from body fluids.
• Tissue Specificity: Brain white matter, skeletal muscle, kidney, adrenal glands, lung and liver.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Histidine metabolism (hsa00340)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Aspartate and asparagine metabolism (R-HSA-8963693)
• BioCyc Pathway: MetaCyc:HS03094-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Canavan disease	DIS7UPG8	Definitive	Autosomal recessive	[1]
Mild Canavan disease	DISHWWRO	Supportive	Autosomal recessive	[2]
Severe Canavan disease	DISLCY56	Supportive	Autosomal recessive	[2]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Aspartoacylase (ASPA).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aspartoacylase (ASPA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aspartoacylase (ASPA).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Aspartoacylase (ASPA).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Aspartoacylase (ASPA).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Aspartoacylase (ASPA).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Aspartoacylase (ASPA).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Aspartoacylase (ASPA).	[10]
Edetic acid	DM10D85	Investigative	Edetic acid decreases the activity of Aspartoacylase (ASPA).	[11]

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] Canavan Disease. 1999 Sep 16 [updated 2023 Dec 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Identification of the zinc binding ligands and the catalytic residue in human aspartoacylase, an enzyme involved in Canavan disease. FEBS Lett. 2006 Oct 30;580(25):5899-904. doi: 10.1016/j.febslet.2006.09.056. Epub 2006 Oct 2.