Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRJQ16X)

• DOT Name: Leucine carboxyl methyltransferase 1 (LCMT1)
• Synonyms: EC 2.1.1.233; Protein-leucine O-methyltransferase; -leucine-carboxy methyltransferase 1
• Gene Name: LCMT1
• Related Disease:
  Adult glioblastoma
  Alzheimer disease
  Glioblastoma multiforme
  Progressive supranuclear palsy
  Tauopathy
  Neuroblastoma
• UniProt ID: LCMT1_HUMAN
• PDB ID: 3IEI; 3O7W; 3P71
• EC Number: 2.1.1.233
• Pfam ID: PF04072
• Sequence:
  MATRQRESSITSCCSTSSCDADDEGVRGTCEDASLCKRFAVSIGYWHDPYIQHFVRLSKE
  RKAPEINRGYFARVHGVSQLIKAFLRKTECHCQIVNLGAGMDTTFWRLKDEDLLPSKYFE
  VDFPMIVTRKLHSIKCKPPLSSPILELHSEDTLQMDGHILDSKRYAVIGADLRDLSELEE
  KLKKCNMNTQLPTLLIAECVLVYMTPEQSANLLKWAANSFERAMFINYEQVNMGDRFGQI
  MIENLRRRQCDLAGVETCKSLESQKERLLSNGWETASAVDMMELYNRLPRAEVSRIESLE
  FLDEMELLEQLMRHYCLCWATKGGNELGLKEITY
• Function: Methylates the carboxyl group of the C-terminal leucine residue of protein phosphatase 2A catalytic subunits to form alpha-leucine ester residues.
• Reactome Pathway: Cyclin A/B1/B2 associated events during G2/M transition (R-HSA-69273)
• BioCyc Pathway: MetaCyc:MONOMER-16510

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[1]
Progressive supranuclear palsy	DISO5KRQ	Strong	Genetic Variation	[2]
Tauopathy	DISY2IPA	Strong	Genetic Variation	[2]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[3]

9 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 Leucine carboxyl methyltransferase 1 (LCMT1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[8]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Leucine carboxyl methyltransferase 1 (LCMT1).	[13]

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 Leucine carboxyl methyltransferase 1 (LCMT1).	[9]

References

• [1] NNMT Silencing Activates Tumor Suppressor PP2A, Inactivates Oncogenic STKs, and Inhibits Tumor Forming Ability.Clin Cancer Res. 2017 May 1;23(9):2325-2334. doi: 10.1158/1078-0432.CCR-16-1323. Epub 2016 Nov 3.
• [2] Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.J Neuropathol Exp Neurol. 2018 Feb 1;77(2):139-148. doi: 10.1093/jnen/nlx110.
• [3] Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells.J Biol Chem. 2013 Sep 20;288(38):27396-27405. doi: 10.1074/jbc.M113.490102. Epub 2013 Aug 13.
• [4] 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.
• [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] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.