Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW1GLEM)

• DOT Name: Glutamate decarboxylase 2 (GAD2)
• Synonyms: EC 4.1.1.15; 65 kDa glutamic acid decarboxylase; GAD-65; Glutamate decarboxylase 65 kDa isoform
• Gene Name: GAD2
• UniProt ID: DCE2_HUMAN
• PDB ID: 1ES0; 2OKK
• EC Number: 4.1.1.15
• Pfam ID: PF00282
• Sequence:
  MASPGSGFWSFGSEDGSGDSENPGTARAWCQVAQKFTGGIGNKLCALLYGDAEKPAESGG
  SQPPRAAARKAACACDQKPCSCSKVDVNYAFLHATDLLPACDGERPTLAFLQDVMNILLQ
  YVVKSFDRSTKVIDFHYPNELLQEYNWELADQPQNLEEILMHCQTTLKYAIKTGHPRYFN
  QLSTGLDMVGLAADWLTSTANTNMFTYEIAPVFVLLEYVTLKKMREIIGWPGGSGDGIFS
  PGGAISNMYAMMIARFKMFPEVKEKGMAALPRLIAFTSEHSHFSLKKGAAALGIGTDSVI
  LIKCDERGKMIPSDLERRILEAKQKGFVPFLVSATAGTTVYGAFDPLLAVADICKKYKIW
  MHVDAAWGGGLLMSRKHKWKLSGVERANSVTWNPHKMMGVPLQCSALLVREEGLMQNCNQ
  MHASYLFQQDKHYDLSYDTGDKALQCGRHVDVFKLWLMWRAKGTTGFEAHVDKCLELAEY
  LYNIIKNREGYEMVFDGKPQHTNVCFWYIPPSLRTLEDNEERMSRLSKVAPVIKARMMEY
  GTTMVSYQPLGDKVNFFRMVISNPAATHQDIDFLIEEIERLGQDL
• Function: Catalyzes the production of GABA.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  beta-Alanine metabolism (hsa00410)
  Taurine and hypotaurine metabolism (hsa00430)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
  GABAergic sy.pse (hsa04727)
  Type I diabetes mellitus (hsa04940)
• Reactome Pathway:
  GABA synthesis, release, reuptake and degradation (R-HSA-888590)
  MECP2 regulates transcription of genes involved in GABA signaling (R-HSA-9022927)
  GABA synthesis (R-HSA-888568)
• BioCyc Pathway: MetaCyc:HS06208-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 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 Glutamate decarboxylase 2 (GAD2).	[1]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glutamate decarboxylase 2 (GAD2).	[4]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Glutamate decarboxylase 2 (GAD2).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glutamate decarboxylase 2 (GAD2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Glutamate decarboxylase 2 (GAD2).	[5]

6 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Malathion	DMXZ84M	Approved	Malathion affects the binding of Glutamate decarboxylase 2 (GAD2).	[3]
Isoflurophate	DMBSK7X	Approved	Isoflurophate affects the binding of Glutamate decarboxylase 2 (GAD2).	[3]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the binding of Glutamate decarboxylase 2 (GAD2).	[3]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos affects the binding of Glutamate decarboxylase 2 (GAD2).	[3]
Paraoxon	DMN4ZKC	Investigative	Paraoxon affects the binding of Glutamate decarboxylase 2 (GAD2).	[3]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon affects the binding of Glutamate decarboxylase 2 (GAD2).	[3]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [3] Decarboxylases as hypothetical targets for actions of organophosphates: Molecular modeling for prediction of hidden and unexpected health threats. Food Chem Toxicol. 2022 Mar;161:112856. doi: 10.1016/j.fct.2022.112856. Epub 2022 Feb 11.
• [4] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [5] 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.
• [6] Direct effect of 2-palmitoyl glycerol on promotion of gamma aminobutyric acid synthesis in normal human fetal-derived astrocytes. FEBS Open Bio. 2023 Jul;13(7):1320-1332. doi: 10.1002/2211-5463.13649. Epub 2023 May 24.