Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSIZU8Y)

• DOT Name: Acyl-coenzyme A thioesterase THEM4 (THEM4)
• Synonyms: Acyl-CoA thioesterase THEM4; EC 3.1.2.2; Carboxyl-terminal modulator protein; Thioesterase superfamily member 4
• Gene Name: THEM4
• Related Disease:
  Amyotrophic lateral sclerosis
  Chronic kidney disease
  Chronic renal failure
  Neoplasm
  Advanced cancer
  Attention deficit hyperactivity disorder
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Obesity
  Pancreatic adenocarcinoma
  Type-1/2 diabetes
  Adult glioblastoma
  Glioblastoma multiforme
  Glioma
  Non-insulin dependent diabetes
• UniProt ID: THEM4_HUMAN
• PDB ID: 4AE8; 4GAH
• EC Number: 3.1.2.2
• Pfam ID: PF03061
• Sequence:
  MLRSCAARLRTLGALCLPPVGRRLPGSEPRPELRSFSSEEVILKDCSVPNPSWNKDLRLL
  FDQFMKKCEDGSWKRLPSYKRTPTEWIQDFKTHFLDPKLMKEEQMSQAQLFTRSFDDGLG
  FEYVMFYNDIEKRMVCLFQGGPYLEGPPGFIHGGAIATMIDATVGMCAMMAGGIVMTANL
  NINYKRPIPLCSVVMINSQLDKVEGRKFFVSCNVQSVDEKTLYSEATSLFIKLNPAKSLT
• Function: Has acyl-CoA thioesterase activity towards medium and long-chain (C14 to C18) fatty acyl-CoA substrates, and probably plays a role in mitochondrial fatty acid metabolism. Plays a role in the apoptotic process, possibly via its regulation of AKT1 activity. According to PubMed:11598301, inhibits AKT1 phosphorylation and activity. According to PubMed:17615157, enhances AKT1 activity by favoring its phosphorylation and translocation to plasma membrane.
• Tissue Specificity: Expressed predominantly in skeletal muscle, testis, uterus, brain and kidney. Down-regulated in glioblastoma or glioma compared to non-neoplastic brain due to promoter hypermethylation.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Metabolic pathways (hsa01100)
  PI3K-Akt sig.ling pathway (hsa04151)
• Reactome Pathway:
  Activation of AKT2 (R-HSA-165158)
  Negative regulation of the PI3K/AKT network (R-HSA-199418)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Mitochondrial Fatty Acid Beta-Oxidation (R-HSA-77289)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Definitive	Altered Expression	[1]
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[2]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Therapeutic	[3]
Liver cancer	DISDE4BI	Strong	Biomarker	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[11]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[12]
Glioblastoma multiforme	DISK8246	Limited	Posttranslational Modification	[13]
Glioma	DIS5RPEH	Limited	Altered Expression	[12]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[14]

11 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 Acyl-coenzyme A thioesterase THEM4 (THEM4).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[20]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[24]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[25]

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 affects the methylation of Acyl-coenzyme A thioesterase THEM4 (THEM4).	[22]

References

• [1] Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis.Sci Rep. 2019 Mar 8;9(1):3920. doi: 10.1038/s41598-019-40553-2.
• [2] Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.J Am Soc Nephrol. 2018 May;29(5):1513-1524. doi: 10.1681/ASN.2017101099. Epub 2018 Mar 15.
• [3] Co-delivery of LETM1 and CTMP synergistically inhibits tumor growth in H-ras12V liver cancer model mice.Cancer Gene Ther. 2013 Mar;20(3):186-94. doi: 10.1038/cgt.2013.6. Epub 2013 Feb 8.
• [4] Translational control and the cancer cell response to stress.Curr Opin Cell Biol. 2017 Apr;45:102-109. doi: 10.1016/j.ceb.2017.05.007. Epub 2017 Jun 2.
• [5] In Vitro Neurochemical Assessment of Methylphenidate and Its "Legal High" Analogs 3,4-CTMP and Ethylphenidate in Rat Nucleus Accumbens and Bed Nucleus of the Stria Terminalis.Front Psychiatry. 2018 May 28;9:149. doi: 10.3389/fpsyt.2018.00149. eCollection 2018.
• [6] CTMP, a predictive biomarker for trastuzumab resistance in HER2-enriched breast cancer patient.Oncotarget. 2017 May 2;8(18):29699-29710. doi: 10.18632/oncotarget.10719.
• [7] Carboxyl-Terminal Modulator Protein Positively Acts as an Oncogenic Driver in Head and Neck Squamous Cell Carcinoma via Regulating Akt phosphorylation.Sci Rep. 2016 Jun 22;6:28503. doi: 10.1038/srep28503.
• [8] Carboxyl-terminal modulator protein induces apoptosis by regulating mitochondrial function in lung cancer cells.Int J Oncol. 2012 May;40(5):1515-24. doi: 10.3892/ijo.2011.1319. Epub 2011 Dec 23.
• [9] Carboxyl-Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B Signaling Pathway.J Am Heart Assoc. 2018 Jun 26;7(13):e008654. doi: 10.1161/JAHA.118.008654.
• [10] Targeting AKT with the proapoptotic peptide, TAT-CTMP: a novel strategy for the treatment of human pancreatic adenocarcinoma.Int J Cancer. 2009 Aug 15;125(4):942-51. doi: 10.1002/ijc.24424.
• [11] New players in high fat diet-induced obesity: LETM1 and CTMP.Metabolism. 2014 Mar;63(3):318-27. doi: 10.1016/j.metabol.2013.10.012. Epub 2013 Oct 31.
• [12] Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas.J Natl Cancer Inst. 2004 Mar 17;96(6):483-6. doi: 10.1093/jnci/djh064.
• [13] Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas.Neuropathol Appl Neurobiol. 2005 Oct;31(5):486-90. doi: 10.1111/j.1365-2990.2005.00660.x.
• [14] Allelic expression imbalance screening of genes in chromosome 1q21-24 region to identify functional variants for Type 2 diabetes susceptibility.Physiol Genomics. 2013 Jul 2;45(13):509-20. doi: 10.1152/physiolgenomics.00048.2013. Epub 2013 May 14.
• [15] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] 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.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.