Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9FSSX0)

• DOT Name: N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2)
• Synonyms: EC 3.4.17.21; Glutamate carboxypeptidase III; GCPIII; N-acetylated-alpha-linked acidic dipeptidase II; NAALADase II
• Gene Name: NAALAD2
• UniProt ID: NALD2_HUMAN
• PDB ID: 3FEC; 3FED; 3FEE; 3FF3
• EC Number: 3.4.17.21
• Pfam ID: PF02225 ; PF04389 ; PF04253
• Sequence:
  MAESRGRLYLWMCLAAALASFLMGFMVGWFIKPLKETTTSVRYHQSIRWKLVSEMKAENI
  KSFLRSFTKLPHLAGTEQNFLLAKKIQTQWKKFGLDSAKLVHYDVLLSYPNETNANYISI
  VDEHETEIFKTSYLEPPPDGYENVTNIVPPYNAFSAQGMPEGDLVYVNYARTEDFFKLER
  EMGINCTGKIVIARYGKIFRGNKVKNAMLAGAIGIILYSDPADYFAPEVQPYPKGWNLPG
  TAAQRGNVLNLNGAGDPLTPGYPAKEYTFRLDVEEGVGIPRIPVHPIGYNDAEILLRYLG
  GIAPPDKSWKGALNVSYSIGPGFTGSDSFRKVRMHVYNINKITRIYNVVGTIRGSVEPDR
  YVILGGHRDSWVFGAIDPTSGVAVLQEIARSFGKLMSKGWRPRRTIIFASWDAEEFGLLG
  STEWAEENVKILQERSIAYINSDSSIEGNYTLRVDCTPLLYQLVYKLTKEIPSPDDGFES
  KSLYESWLEKDPSPENKNLPRINKLGSGSDFEAYFQRLGIASGRARYTKNKKTDKYSSYP
  VYHTIYETFELVEKFYDPTFKKQLSVAQLRGALVYELVDSKIIPFNIQDYAEALKNYAAS
  IYNLSKKHDQQLTDHGVSFDSLFSAVKNFSEAASDFHKRLIQVDLNNPIAVRMMNDQLML
  LERAFIDPLGLPGKLFYRHIIFAPSSHNKYAGESFPGIYDAIFDIENKANSRLAWKEVKK
  HISIAAFTIQAAAGTLKEVL
• Function: Has N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) activity. Also exhibits a dipeptidyl-peptidase IV type activity. Inactivates the peptide neurotransmitter N-acetylaspartylglutamate.
• Tissue Specificity: Highest expression in the testis. Also found in ovary and spleen. Weak expression in prostate, heart and placenta. In brain, expressed in striatum, parietal cortex and ventral striatum with lower levels in hippocampus, brain stem, putamen and superior colliculus.
• Reactome Pathway: Aspartate and asparagine metabolism (R-HSA-8963693)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of N-acetylated-alpha-linked acidic dipeptidase 2 (NAALAD2).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.