Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIPTH3Q)

• DOT Name: Alanine--glyoxylate aminotransferase (AGXT)
• Synonyms: AGT; EC 2.6.1.44; Serine--pyruvate aminotransferase; SPT; EC 2.6.1.51
• Gene Name: AGXT
• Related Disease:
  Alanine glyoxylate aminotransferase deficiency
  Primary hyperoxaluria type 1
• UniProt ID: AGT1_HUMAN
• PDB ID: 1H0C; 1J04; 2YOB; 3R9A; 4CBR; 4CBS; 4I8A; 4KXK; 4KYO; 5F9S; 5HHY; 5LUC; 5OFY; 5OG0; 6RV0; 6RV1; 7NS7
• EC Number: 2.6.1.44; 2.6.1.51
• Pfam ID: PF00266
• Sequence:
  MASHKLLVTPPKALLKPLSIPNQLLLGPGPSNLPPRIMAAGGLQMIGSMSKDMYQIMDEI
  KEGIQYVFQTRNPLTLVISGSGHCALEAALVNVLEPGDSFLVGANGIWGQRAVDIGERIG
  ARVHPMTKDPGGHYTLQEVEEGLAQHKPVLLFLTHGESSTGVLQPLDGFGELCHRYKCLL
  LVDSVASLGGTPLYMDRQGIDILYSGSQKALNAPPGTSLISFSDKAKKKMYSRKTKPFSF
  YLDIKWLANFWGCDDQPRMYHHTIPVISLYSLRESLALIAEQGLENSWRQHREAAAYLHG
  RLQALGLQLFVKDPALRLPTVTTVAVPAGYDWRDIVSYVIDHFDIEIMGGLGPSTGKVLR
  IGLLGCNATRENVDRVTEALRAALQHCPKKKL
• Function: Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification. Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism.
• Tissue Specificity: Liver.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Glycine, serine and threonine metabolism (hsa00260)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS10525-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alanine glyoxylate aminotransferase deficiency	DISRQ6HW	Definitive	Autosomal recessive	[1]
Primary hyperoxaluria type 1	DISS210K	Definitive	Autosomal recessive	[1]

12 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 Alanine--glyoxylate aminotransferase (AGXT).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[3]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Alanine--glyoxylate aminotransferase (AGXT).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[7]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[8]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[3]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Alanine--glyoxylate aminotransferase (AGXT).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Alanine--glyoxylate aminotransferase (AGXT).	[10]

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] 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.
• [3] 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.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [9] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.