Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSON89V)

• DOT Name: Guanidino acid hydrolase, mitochondrial (AGMAT)
• Synonyms: EC 3.5.3.-; Arginase, mitochondrial; EC 3.5.3.1; Guanidinobutyrase, mitochondrial; EC 3.5.3.7; Guanidinopropionase, mitochondrial; EC 3.5.3.17
• Gene Name: AGMAT
• UniProt ID: GDAH_HUMAN
• EC Number: 3.5.3.-; 3.5.3.1; 3.5.3.17; 3.5.3.7
• Pfam ID: PF00491
• Sequence:
  MLRLLASGCARGPGPGVGARPAAGLFHPGRRQSRQASDAPRNQPPSPEFVARPVGVCSMM
  RLPVQTSPEGLDAAFIGVPLDTGTSNRPGARFGPRRIREESVMLGTVNPSTGALPFQSLM
  VADLGDVNVNLYNLQDSCRRIQEAYEKIVAAGCIPLTLGGDHTITYPILQAMAKKHGPVG
  LLHVDAHTDTTDKALGEKLYHGAPFRRCVDEGLLDCKRVVQIGIRGSSTTLDPYRYNRSQ
  GFRVVLAEDCWMKSLVPLMGEVRQQMGGKPIYISFDIDALDPAYAPGTGTPEIAGLTPSQ
  ALEIIRGCQGLNVMGCDLVEVSPPYDLSGNTALLAANLLFEMLCALPKVTTV
• Function: Hydrolyzes linear guanidino acids to form urea and the corresponding amines. Displays specificity for substrates having a negatively charged head group and short chains including taurocyamine, guanidino propanoic and butanoic acids. May protect cells by detoxifying potentially harmful amounts of guanidino acids. Metabolizes L-arginine with low efficiency.
• Tissue Specificity: Highly expressed in liver and kidney. Also found in skeletal muscle, fetal liver, brain, testis, skin and the gastrointestinal tract. Within brain, expression is higher in the cerebral cortex with lower levels in the medulla and spinal cord.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Agmatine biosynthesis (R-HSA-351143)
• BioCyc Pathway: MetaCyc:HS04051-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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 Guanidino acid hydrolase, mitochondrial (AGMAT).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[8]
Fenfluramine	DM0762O	Phase 3	Fenfluramine decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Guanidino acid hydrolase, mitochondrial (AGMAT).	[12]

References

• [1] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] 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] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.