Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMS00PY)

• DOT Name: Ethylmalonyl-CoA decarboxylase (ECHDC1)
• Synonyms: EC 4.1.1.94; Enoyl-CoA hydratase domain-containing protein 1; Methylmalonyl-CoA decarboxylase; MMCD
• Gene Name: ECHDC1
• Related Disease:
  Bladder cancer
  Epithelial ovarian cancer
  Melanoma
  Ovarian cancer
  Ovarian neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: ECHD1_HUMAN
• EC Number: 4.1.1.94
• Pfam ID: PF00378
• Sequence:
  MALKQEMAKSLLKTASLSGRTKLLHQTGLSLYSTSHGFYEEEVKKTLQQFPGGSIDLQKE
  DNGIGILTLNNPSRMNAFSGVMMLQLLEKVIELENWTEGKGLIVRGAKNTFSSGSDLNAV
  KSLGTPEDGMAVCMFMQNTLTRFMRLPLISVALVQGWALGGGAEFTTACDFRLMTPESKI
  RFVHKEMGIIPSWGGTTRLVEIIGSRQALKVLSGALKLDSKNALNIGMVEEVLQSSDETK
  SLEEAQEWLKQFIQGPPEVIRALKKSVCSGRELYLEEALQNERDLLGTVWGGPANLEAIA
  KKGKFNK
• Function: Decarboxylates ethylmalonyl-CoA, a potentially toxic metabolite, to form butyryl-CoA, suggesting it might be involved in metabolite proofreading. Acts preferentially on (S)-ethylmalonyl-CoA but has also some activity on the (R)-isomer. Also has methylmalonyl-CoA decarboxylase activity at lower level.
• KEGG Pathway:
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[2]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[11]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[12]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Ethylmalonyl-CoA decarboxylase (ECHDC1).	[15]

References

• [1] Silencing of ECHDC1 inhibits growth of gemcitabine-resistant bladder cancer cells.Oncol Lett. 2018 Jan;15(1):522-527. doi: 10.3892/ol.2017.7269. Epub 2017 Oct 26.
• [2] The RNF146 and ECHDC1 genes as candidates for inherited breast and ovarian cancer in Jewish Ashkenazi women.Fam Cancer. 2009;8(4):399-402. doi: 10.1007/s10689-009-9255-7. Epub 2009 Jun 11.
• [3] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.