Details of Drug Off-Target (DOT)

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

• DOT Name: S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2)
• Synonyms: SMM-hcy methyltransferase; EC 2.1.1.10; Betaine--homocysteine S-methyltransferase 2
• Gene Name: BHMT2
• Related Disease:
  Cleft lip/palate
  Isolated cleft lip
  Isolated cleft palate
  Neoplasm
• UniProt ID: BHMT2_HUMAN
• EC Number: 2.1.1.10
• Pfam ID: PF02574
• Sequence:
  MAPAGRPGAKKGILERLESGEVVIGDGSFLITLEKRGYVKAGLWTPEAVIEHPDAVRQLH
  MEFLRAGSNVMQTFTFSASEDNMESKWEDVNAAACDLAREVAGKGDALVAGGICQTSIYK
  YQKDEARIKKLFRQQLEVFAWKNVDFLIAEYFEHVEEAVWAVEVLKESDRPVAVTMCIGP
  EGDMHDITPGECAVRLVKAGASIVGVNCRFGPDTSLKTMELMKEGLEWAGLKAHLMVQPL
  GFHAPDCGKEGFVDLPEYPFGLESRVATRWDIQKYAREAYNLGVRYIGGCCGFEPYHIRA
  IAEELAPERGFLPPASEKHGSWGSGLDMHTKPWIRARARREYWENLLPASGRPFCPSLSK
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• Function: Involved in the regulation of homocysteine metabolism. Converts homocysteine to methionine using S-methylmethionine (SMM) as a methyl donor.
• Tissue Specificity: Expressed in liver and kidney and at reduced levels in the brain, heart, and skeletal muscle.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sulfur amino acid metabolism (R-HSA-1614635)
• BioCyc Pathway: MetaCyc:HS05696-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[1]
Isolated cleft lip	DIS2O2JV	Strong	Biomarker	[2]
Isolated cleft palate	DISV80CD	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]

7 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 S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of S-methylmethionine--homocysteine S-methyltransferase BHMT2 (BHMT2).	[10]

References

• [1] Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts?.Am J Med Genet A. 2005 Jun 15;135(3):274-7. doi: 10.1002/ajmg.a.30739.
• [2] Folate pathway and nonsyndromic cleft lip and palate.Birth Defects Res A Clin Mol Teratol. 2011 Jan;91(1):50-60. doi: 10.1002/bdra.20740. Epub 2010 Dec 1.
• [3] A splicing variant leads to complete loss of function of betaine-homocysteine methyltransferase (BHMT) gene in hepatocellular carcinoma.Int J Biochem Cell Biol. 2012 Feb;44(2):385-92. doi: 10.1016/j.biocel.2011.11.014. Epub 2011 Nov 26.
• [4] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] 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.
• [11] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.