Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVC87ES)

• DOT Name: Guanidinoacetate N-methyltransferase (GAMT)
• Synonyms: EC 2.1.1.2
• Gene Name: GAMT
• Related Disease:
  Guanidinoacetate methyltransferase deficiency
  Creatine transporter deficiency
  Helminth infection
  Inborn disorder of amino acid metabolism
  Intellectual disability
  Dystonia
  Neoplasm
• UniProt ID: GAMT_HUMAN
• PDB ID: 3ORH
• EC Number: 2.1.1.2
• Sequence:
  MSAPSATPIFAPGENCSPAWGAAPAAYDAADTHLRILGKPVMERWETPYMHALAAAASSK
  GGRVLEVGFGMAIAASKVQEAPIDEHWIIECNDGVFQRLRDWAPRQTHKVIPLKGLWEDV
  APTLPDGHFDGILYDTYPLSEETWHTHQFNFIKNHAFRLLKPGGVLTYCNLTSWGELMKS
  KYSDITIMFEETQVPALLEAGFRRENIRTEVMALVPPADCRYYAFPQMITPLVTKG
• Function: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor. Important in nervous system development.
• Tissue Specificity: Expressed in liver.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Transcriptional Regulation by MECP2 (R-HSA-8986944)
  Creatine metabolism (R-HSA-71288)
• BioCyc Pathway: MetaCyc:HS05327-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Guanidinoacetate methyltransferase deficiency	DIS7L5S0	Definitive	Autosomal recessive	[1]
Creatine transporter deficiency	DIS8FWNV	Strong	Biomarker	[2]
Helminth infection	DIS7CGKY	Strong	Biomarker	[3]
Inborn disorder of amino acid metabolism	DISFWXCM	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Dystonia	DISJLFGW	Limited	Biomarker	[5]
Neoplasm	DISZKGEW	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Guanidinoacetate N-methyltransferase (GAMT) affects the response to substance of Methotrexate.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Guanidinoacetate N-methyltransferase (GAMT).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Guanidinoacetate N-methyltransferase (GAMT).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[13]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[14]
Ammonia	DMOEVK6	Approved	Ammonia increases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Guanidinoacetate N-methyltransferase (GAMT).	[20]

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] Cerebral creatine deficiencies: a group of treatable intellectual developmental disorders.Semin Neurol. 2014 Jul;34(3):350-6. doi: 10.1055/s-0034-1386772. Epub 2014 Sep 5.
• [3] Sequence and immunogenicity of the Taenia saginata homologue of the major surface antigen of Echinococcus spp.Parasitol Res. 1998 May;84(5):426-31. doi: 10.1007/s004360050423.
• [4] Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation.Am J Med Genet A. 2005 Mar 1;133A(2):122-7. doi: 10.1002/ajmg.a.30226.
• [5] Guanidinoacetate methyltransferase (GAMT) deficiency: outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring.Mol Genet Metab. 2014 Jan;111(1):16-25. doi: 10.1016/j.ymgme.2013.10.018. Epub 2013 Nov 7.
• [6] Does TP53 mutation promote ovarian cancer metastasis to omentum by regulating lipid metabolism?.Med Hypotheses. 2013 Oct;81(4):515-20. doi: 10.1016/j.mehy.2013.06.009. Epub 2013 Jul 20.
• [7] 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.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [13] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [14] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.