Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT52Z39J)

• DOT Name: Glutamate decarboxylase 1 (GAD1)
• Synonyms: EC 4.1.1.15; 67 kDa glutamic acid decarboxylase; GAD-67; Glutamate decarboxylase 67 kDa isoform
• Gene Name: GAD1
• Related Disease:
  Obsolete early infantile epileptic encephalopathy
  Developmental and epileptic encephalopathy 89
  Spastic quadriplegic cerebral palsy
  Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
  Obsolete cerebral palsy, spastic quadriplegic, 1
• UniProt ID: DCE1_HUMAN
• PDB ID: 2OKJ; 3VP6
• EC Number: 4.1.1.15
• Pfam ID: PF00282
• Sequence:
  MASSTPSSSATSSNAGADPNTTNLRPTTYDTWCGVAHGCTRKLGLKICGFLQRTNSLEEK
  SRLVSAFKERQSSKNLLSCENSDRDARFRRTETDFSNLFARDLLPAKNGEEQTVQFLLEV
  VDILLNYVRKTFDRSTKVLDFHHPHQLLEGMEGFNLELSDHPESLEQILVDCRDTLKYGV
  RTGHPRFFNQLSTGLDIIGLAGEWLTSTANTNMFTYEIAPVFVLMEQITLKKMREIVGWS
  SKDGDGIFSPGGAISNMYSIMAARYKYFPEVKTKGMAAVPKLVLFTSEQSHYSIKKAGAA
  LGFGTDNVILIKCNERGKIIPADFEAKILEAKQKGYVPFYVNATAGTTVYGAFDPIQEIA
  DICEKYNLWLHVDAAWGGGLLMSRKHRHKLNGIERANSVTWNPHKMMGVLLQCSAILVKE
  KGILQGCNQMCAGYLFQPDKQYDVSYDTGDKAIQCGRHVDIFKFWLMWKAKGTVGFENQI
  NKCLELAEYLYAKIKNREEFEMVFNGEPEHTNVCFWYIPQSLRGVPDSPQRREKLHKVAP
  KIKALMMESGTTMVGYQPQGDKANFFRMVISNPAATQSDIDFLIEEIERLGQDL
• Function: Catalyzes the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) with pyridoxal 5'-phosphate as cofactor; [Isoform 3]: Enzymatically inactive as glutamate decarboxylase.
• Tissue Specificity: .Expressed in brain.; [Isoform 3]: Expressed in pancreatic islets, testis, adrenal cortex, and perhaps other endocrine tissues, but not in brain.
• 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:HS05215-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete early infantile epileptic encephalopathy	DISTX26B	Definitive	Autosomal recessive	[1]
Developmental and epileptic encephalopathy 89	DISSIV2G	Strong	Autosomal recessive	[2]
Spastic quadriplegic cerebral palsy	DISBJRHC	Supportive	Autosomal recessive	[3]
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	DIS4YFC4	Limited	Autosomal recessive	[3]
Obsolete cerebral palsy, spastic quadriplegic, 1	DIS3AA82	Limited	Autosomal recessive	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Glutamate decarboxylase 1 (GAD1) decreases the response to substance of Hydrogen peroxide.	[24]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
GSK683699	DMTW79H	Phase 2	Glutamate decarboxylase 1 (GAD1) increases the chemical synthesis of GSK683699.	[3]

21 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 1 (GAD1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutamate decarboxylase 1 (GAD1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutamate decarboxylase 1 (GAD1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Glutamate decarboxylase 1 (GAD1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glutamate decarboxylase 1 (GAD1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Glutamate decarboxylase 1 (GAD1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Glutamate decarboxylase 1 (GAD1).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glutamate decarboxylase 1 (GAD1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glutamate decarboxylase 1 (GAD1).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Glutamate decarboxylase 1 (GAD1).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Glutamate decarboxylase 1 (GAD1).	[13]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Glutamate decarboxylase 1 (GAD1).	[16]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Glutamate decarboxylase 1 (GAD1).	[18]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Glutamate decarboxylase 1 (GAD1).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glutamate decarboxylase 1 (GAD1).	[13]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Glutamate decarboxylase 1 (GAD1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Glutamate decarboxylase 1 (GAD1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glutamate decarboxylase 1 (GAD1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutamate decarboxylase 1 (GAD1).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Glutamate decarboxylase 1 (GAD1).	[22]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of Glutamate decarboxylase 1 (GAD1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Glutamate decarboxylase 1 (GAD1).	[11]

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 1 (GAD1).	[17]
Isoflurophate	DMBSK7X	Approved	Isoflurophate affects the binding of Glutamate decarboxylase 1 (GAD1).	[17]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the binding of Glutamate decarboxylase 1 (GAD1).	[17]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos affects the binding of Glutamate decarboxylase 1 (GAD1).	[17]
Paraoxon	DMN4ZKC	Investigative	Paraoxon affects the binding of Glutamate decarboxylase 1 (GAD1).	[17]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon affects the binding of Glutamate decarboxylase 1 (GAD1).	[17]

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] Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy. Brain. 2020 May 1;143(5):1447-1461. doi: 10.1093/brain/awaa085.
• [3] Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders. BMC Neurol. 2004 Nov 30;4(1):20. doi: 10.1186/1471-2377-4-20.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol. 2007 Mar;71(3):644-53. doi: 10.1124/mol.106.030635. Epub 2006 Oct 25.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [11] Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol. 2013 Feb;27(2):106-15. doi: 10.1002/jbt.21462. Epub 2013 Jan 11.
• [12] 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.
• [13] 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.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [16] Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci. 2007 Oct 17;27(42):11254-62. doi: 10.1523/JNEUROSCI.3272-07.2007.
• [17] 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.
• [18] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [23] 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.
• [24] GAD 67KD antisense in colon cancer cells inhibits cell growth and sensitizes to butyrate and pH reduction and H2O2 and gamma-radiation. Arch Biochem Biophys. 2004 Oct 15;430(2):229-36. doi: 10.1016/j.abb.2004.07.015.