Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0O2OQO)

• DOT Name: Glycine N-methyltransferase (GNMT)
• Synonyms: EC 2.1.1.20
• Gene Name: GNMT
• Related Disease:
  Acute myelogenous leukaemia
  Liver cirrhosis
  Non-alcoholic fatty liver disease
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Cholangiocarcinoma
  Cholestasis
  Disorder of methionine catabolism
  Fatty liver disease
  Glycine N-methyltransferase deficiency
  Hepatitis
  Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
  Inborn error of metabolism
  Liver cancer
  Matthew-Wood syndrome
  Methionine adenosyltransferase deficiency
  Neoplasm
  Nephropathy
  Pancreatic adenocarcinoma
  Prostate carcinoma
  Schizophrenia
  Melanoma
  Prostate cancer
  Breast cancer
  Breast carcinoma
  Metastatic prostate carcinoma
  Non-alcoholic steatohepatitis
  Prostate neoplasm
• UniProt ID: GNMT_HUMAN
• PDB ID: 1R74; 2AZT
• EC Number: 2.1.1.20
• Pfam ID: PF13649
• Sequence:
  MVDSVYRTRSLGVAAEGLPDQYADGEAARVWQLYIGDTRSRTAEYKAWLLGLLRQHGCQR
  VLDVACGTGVDSIMLVEEGFSVTSVDASDKMLKYALKERWNRRHEPAFDKWVIEEANWMT
  LDKDVPQSAEGGFDAVICLGNSFAHLPDCKGDQSEHRLALKNIASMVRAGGLLVIDHRNY
  DHILSTGCAPPGKNIYYKSDLTKDVTTSVLIVNNKAHMVTLDYTVQVPGAGQDGSPGLSK
  FRLSYYPHCLASFTELLQAAFGGKCQHSVLGDFKPYKPGQTYIPCYFIHVLKRTD
• Function: Catalyzes the methylation of glycine by using S-adenosylmethionine (AdoMet) to form N-methylglycine (sarcosine) with the concomitant production of S-adenosylhomocysteine (AdoHcy), a reaction regulated by the binding of 5-methyltetrahydrofolate. Plays an important role in the regulation of methyl group metabolism by regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L-homocysteine.
• Tissue Specificity: Expressed only in liver, pancreas, and prostate.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
  Metabolism of ingested SeMet, Sec, MeSec into H2Se (R-HSA-2408508)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Posttranslational Modification	[1]
Liver cirrhosis	DIS4G1GX	Definitive	Biomarker	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[6]
Cholestasis	DISDJJWE	Strong	Biomarker	[7]
Disorder of methionine catabolism	DISC7OZE	Strong	Biomarker	[8]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[9]
Glycine N-methyltransferase deficiency	DIS8EP8S	Strong	Autosomal recessive	[10]
Hepatitis	DISXXX35	Strong	Biomarker	[11]
Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase	DISI3RCT	Strong	Biomarker	[8]
Inborn error of metabolism	DISO5FAY	Strong	Genetic Variation	[12]
Liver cancer	DISDE4BI	Strong	Altered Expression	[5]
Matthew-Wood syndrome	DISA7HR7	Strong	Posttranslational Modification	[13]
Methionine adenosyltransferase deficiency	DIS4SI69	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Nephropathy	DISXWP4P	Strong	Biomarker	[15]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[16]
Schizophrenia	DISSRV2N	Strong	Biomarker	[17]
Melanoma	DIS1RRCY	moderate	Biomarker	[18]
Prostate cancer	DISF190Y	moderate	Genetic Variation	[16]
Breast cancer	DIS7DPX1	Limited	Biomarker	[19]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[19]
Metastatic prostate carcinoma	DISVBEZ9	Limited	Biomarker	[16]
Non-alcoholic steatohepatitis	DIST4788	Limited	Altered Expression	[3]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[20]

20 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 Glycine N-methyltransferase (GNMT).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycine N-methyltransferase (GNMT).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycine N-methyltransferase (GNMT).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glycine N-methyltransferase (GNMT).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glycine N-methyltransferase (GNMT).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycine N-methyltransferase (GNMT).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Glycine N-methyltransferase (GNMT).	[26]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Glycine N-methyltransferase (GNMT).	[26]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Glycine N-methyltransferase (GNMT).	[27]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Glycine N-methyltransferase (GNMT).	[28]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Glycine N-methyltransferase (GNMT).	[27]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Glycine N-methyltransferase (GNMT).	[29]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Glycine N-methyltransferase (GNMT).	[30]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Glycine N-methyltransferase (GNMT).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glycine N-methyltransferase (GNMT).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glycine N-methyltransferase (GNMT).	[31]
PIRINIXIC ACID	DM82Y75	Preclinical	PIRINIXIC ACID decreases the expression of Glycine N-methyltransferase (GNMT).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Glycine N-methyltransferase (GNMT).	[32]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Glycine N-methyltransferase (GNMT).	[33]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Glycine N-methyltransferase (GNMT).	[34]

References

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• [5] Gene Expression and DNA Methylation Alterations in the Glycine N-Methyltransferase Gene in Diet-Induced Nonalcoholic Fatty Liver Disease-Associated Carcinogenesis.Toxicol Sci. 2019 Aug 1;170(2):273-282. doi: 10.1093/toxsci/kfz110.
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• [12] Choline-related-inherited metabolic diseases-A mini review.J Inherit Metab Dis. 2019 Mar;42(2):237-242. doi: 10.1002/jimd.12011. Epub 2019 Jan 25.
• [13] Epigenetic Silencing of GNMT Gene in Pancreatic Adenocarcinoma.Cancer Genomics Proteomics. 2015 Jan-Feb;12(1):21-30.
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• [16] Genetic polymorphisms of the glycine N-methyltransferase and prostate cancer risk in the health professionals follow-up study.PLoS One. 2014 May 6;9(5):e94683. doi: 10.1371/journal.pone.0094683. eCollection 2014.
• [17] Characterization of the neuropsychological phenotype of glycine N-methyltransferase-/- mice and evaluation of its responses to clozapine and sarcosine treatments.Eur Neuropsychopharmacol. 2012 Aug;22(8):596-606. doi: 10.1016/j.euroneuro.2011.12.007. Epub 2012 Jan 20.
• [18] Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy.J Invest Dermatol. 2014 Dec;134(12):2957-2966. doi: 10.1038/jid.2014.270. Epub 2014 Jul 7.
• [19] Implications of differences in expression of sarcosine metabolism-related proteins according to the molecular subtype of breast cancer.J Transl Med. 2014 May 28;12:149. doi: 10.1186/1479-5876-12-149.
• [20] The role of sarcosine metabolism in prostate cancer progression.Neoplasia. 2013 May;15(5):491-501. doi: 10.1593/neo.13314.
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• [22] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
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• [28] Use of transcriptomics in hazard identification and next generation risk assessment: A case study with clothianidin. Food Chem Toxicol. 2022 Aug;166:113212. doi: 10.1016/j.fct.2022.113212. Epub 2022 Jun 8.
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• [32] 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.
• [33] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [34] Identification of early target genes of aflatoxin B1 in human hepatocytes, inter-individual variability and comparison with other genotoxic compounds. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):176-87.