Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIJ4Z11)

• DOT Name: Glycine amidinotransferase, mitochondrial (GATM)
• Synonyms: EC 2.1.4.1; L-arginine:glycine amidinotransferase; Transamidinase
• Gene Name: GATM
• Related Disease:
  AGAT deficiency
  Carcinoma
  Chronic renal failure
  Guanidinoacetate methyltransferase deficiency
  Behcet disease
  Cardiac failure
  Congestive heart failure
  Creatine transporter deficiency
  Endometriosis
  Myocardial ischemia
  Nephropathy
  Renal cell carcinoma
  Type-1/2 diabetes
  Fanconi renotubular syndrome 1
  Prostate cancer
  Prostate carcinoma
  Stroke
  Primary Fanconi syndrome
  Acute kidney injury
  Primary biliary cholangitis
  Undifferentiated carcinoma
• UniProt ID: GATM_HUMAN
• PDB ID: 1JDW; 1JDX; 2JDW; 2JDX; 3JDW; 4JDW; 5JDW; 6JDW; 7JDW; 8JDW; 9JDW
• EC Number: 2.1.4.1
• Sequence:
  MLRVRCLRGGSRGAEAVHYIGSRLGRTLTGWVQRTFQSTQAATASSRNSCAADDKATEPL
  PKDCPVSSYNEWDPLEEVIVGRAENACVPPFTIEVKANTYEKYWPFYQKQGGHYFPKDHL
  KKAVAEIEEMCNILKTEGVTVRRPDPIDWSLKYKTPDFESTGLYSAMPRDILIVVGNEII
  EAPMAWRSRFFEYRAYRSIIKDYFHRGAKWTTAPKPTMADELYNQDYPIHSVEDRHKLAA
  QGKFVTTEFEPCFDAADFIRAGRDIFAQRSQVTNYLGIEWMRRHLAPDYRVHIISFKDPN
  PMHIDATFNIIGPGIVLSNPDRPCHQIDLFKKAGWTIITPPTPIIPDDHPLWMSSKWLSM
  NVLMLDEKRVMVDANEVPIQKMFEKLGITTIKVNIRNANSLGGGFHCWTCDVRRRGTLQS
  YLD
• Function: Transamidinase that catalyzes the transfer of the amidino group of L-arginine onto the amino moiety of acceptor metabolites such as glycine, beta-alanine, gamma-aminobutyric acid (GABA) and taurine yielding the corresponding guanidine derivatives. Catalyzes the rate-limiting step of creatine biosynthesis, namely the transfer of the amidino group from L-arginine to glycine to generate guanidinoacetate, which is then methylated by GAMT to form creatine. Provides creatine as a source for ATP generation in tissues with high energy demands, in particular skeletal muscle, heart and brain (Probable).
• Tissue Specificity: Expressed in brain, heart, kidney, liver, lung, salivary gland and skeletal muscle tissue, with the highest expression in kidney. Biallelically expressed in placenta and fetal tissues.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Creatine metabolism (R-HSA-71288)
• BioCyc Pathway: MetaCyc:HS10376-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
AGAT deficiency	DISS7IGD	Definitive	Autosomal recessive	[1]
Carcinoma	DISH9F1N	Definitive	Biomarker	[2]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[3]
Guanidinoacetate methyltransferase deficiency	DIS7L5S0	Definitive	Biomarker	[4]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[5]
Cardiac failure	DISDC067	Strong	Altered Expression	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[6]
Creatine transporter deficiency	DIS8FWNV	Strong	Biomarker	[7]
Endometriosis	DISX1AG8	Strong	Biomarker	[8]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[9]
Nephropathy	DISXWP4P	Strong	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[11]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[12]
Fanconi renotubular syndrome 1	DIS30RYU	Moderate	Autosomal dominant	[13]
Prostate cancer	DISF190Y	moderate	Biomarker	[14]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[14]
Stroke	DISX6UHX	moderate	Biomarker	[15]
Primary Fanconi syndrome	DISR144Y	Supportive	Autosomal dominant	[16]
Acute kidney injury	DISXZG0T	Disputed	Biomarker	[17]
Primary biliary cholangitis	DIS43E0O	Disputed	Genetic Variation	[18]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[2]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Creatine ALS-08	DMKD2BQ	Phase 3	Glycine amidinotransferase, mitochondrial (GATM) increases the chemical synthesis of Creatine ALS-08.	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[26]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Glycine amidinotransferase, mitochondrial (GATM).	[27]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[28]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[29]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glycine amidinotransferase, mitochondrial (GATM).	[30]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[31]
Ammonia	DMOEVK6	Approved	Ammonia decreases the activity of Glycine amidinotransferase, mitochondrial (GATM).	[32]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[36]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[40]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[41]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Glycine amidinotransferase, mitochondrial (GATM).	[42]

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] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [3] A catalog of genetic loci associated with kidney function from analyses of a million individuals.Nat Genet. 2019 Jun;51(6):957-972. doi: 10.1038/s41588-019-0407-x. Epub 2019 May 31.
• [4] Di-acetyl creatine ethyl ester, a new creatine derivative for the possible treatment of creatine transporter deficiency.Neurosci Lett. 2018 Feb 5;665:217-223. doi: 10.1016/j.neulet.2017.12.020. Epub 2017 Dec 8.
• [5] SUMO4 gene polymorphisms in Chinese Han patients with Behcet's disease.Clin Immunol. 2008 Oct;129(1):170-5. doi: 10.1016/j.clim.2008.06.006. Epub 2008 Jul 26.
• [6] Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation. 2006 Jul 4;114(1 Suppl):I16-20. doi: 10.1161/CIRCULATIONAHA.105.000448.
• [7] Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder.Int J Mol Sci. 2017 Jul 31;18(8):1665. doi: 10.3390/ijms18081665.
• [8] Association of FCRL3 -169T/C polymorphism with endometriosis and identification of a protective haplotype against the development of the disease in Brazilian population.Hum Immunol. 2011 Sep;72(9):774-8. doi: 10.1016/j.humimm.2011.05.005. Epub 2011 May 24.
• [9] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [10] Integrated transcriptomic and proteomic evaluation of gentamicin nephrotoxicity in rats.Toxicol Appl Pharmacol. 2012 Jan 1;258(1):124-33. doi: 10.1016/j.taap.2011.10.015. Epub 2011 Oct 29.
• [11] Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer.BMC Genomics. 2015 Mar 27;16(1):247. doi: 10.1186/s12864-015-1446-z.
• [12] Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
• [13] 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.
• [14] Copy number alterations in prostate tumors and disease aggressiveness.Genes Chromosomes Cancer. 2012 Jan;51(1):66-76. doi: 10.1002/gcc.20932. Epub 2011 Oct 2.
• [15] Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.Circulation. 2013 Sep 24;128(13):1451-61. doi: 10.1161/CIRCULATIONAHA.112.000580. Epub 2013 Sep 4.
• [16] Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure. J Am Soc Nephrol. 2018 Jul;29(7):1849-1858. doi: 10.1681/ASN.2017111179. Epub 2018 Apr 13.
• [17] Interrelation of urinary and plasma levels of guanidinoacetic acid with alteration in renal activity of glycine amidinotransferase in acute renal failure rats.Chem Pharm Bull (Tokyo). 1989 Mar;37(3):781-4. doi: 10.1248/cpb.37.781.
• [18] Genetic polymorphisms in CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliary cirrhosis in Japanese patients.J Gastroenterol. 2011 Oct;46(10):1203-12. doi: 10.1007/s00535-011-0417-7. Epub 2011 May 19.
• [19] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [20] 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.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] 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.
• [26] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [27] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [28] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [29] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [30] 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.
• [31] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [32] Ammonia toxicity to the brain: effects on creatine metabolism and transport and protective roles of creatine. Mol Genet Metab. 2010;100 Suppl 1:S53-8. doi: 10.1016/j.ymgme.2010.02.011. Epub 2010 Feb 14.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] 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.
• [35] 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.
• [36] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [37] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [38] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [39] 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.
• [40] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [41] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [42] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [43] Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis. Circulation. 2006 Jul 4;114(1 Suppl):I16-20. doi: 10.1161/CIRCULATIONAHA.105.000448.