Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP7Y0UF)

• DOT Name: Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL)
• Synonyms: LCAD; EC 1.3.8.8
• Gene Name: ACADL
• Related Disease:
  Chronic kidney disease
  Chronic renal failure
  Advanced cancer
  Esophageal squamous cell carcinoma
  Neoplasm
  Very long chain acyl-CoA dehydrogenase deficiency
  Hypoglycemia
  Long chain acyl-CoA dehydrogenase deficiency
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
• UniProt ID: ACADL_HUMAN
• EC Number: 1.3.8.8
• Pfam ID: PF00441 ; PF02770 ; PF02771
• Sequence:
  MAARLLRGSLRVLGGHRAPRQLPAARCSHSGGEERLETPSAKKLTDIGIRRIFSPEHDIF
  RKSVRKFFQEEVIPHHSEWEKAGEVSREVWEKAGKQGLLGVNIAEHLGGIGGDLYSAAIV
  WEEQAYSNCSGPGFSIHSGIVMSYITNHGSEEQIKHFIPQMTAGKCIGAIAMTEPGAGSD
  LQGIKTNAKKDGSDWILNGSKVFISNGSLSDVVIVVAVTNHEAPSPAHGISLFLVENGMK
  GFIKGRKLHKMGLKAQDTAELFFEDIRLPASALLGEENKGFYYIMKELPQERLLIADVAI
  SASEFMFEETRNYVKQRKAFGKTVAHLQTVQHKLAELKTHICVTRAFVDNCLQLHEAKRL
  DSATACMAKYWASELQNSVAYDCVQLHGGWGYMWEYPIAKAYVDARVQPIYGGTNEIMKE
  LIAREIVFDK
• Function: Long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation, an aerobic process breaking down fatty acids into acetyl-CoA and allowing the production of energy from fats. The first step of fatty acid beta-oxidation consists in the removal of one hydrogen from C-2 and C-3 of the straight-chain fatty acyl-CoA thioester, resulting in the formation of trans-2-enoyl-CoA. Among the different mitochondrial acyl-CoA dehydrogenases, long-chain specific acyl-CoA dehydrogenase can act on saturated and unsaturated acyl-CoAs with 6 to 24 carbons with a preference for 8 to 18 carbons long primary chains.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
  PPAR sig.ling pathway (hsa03320)
• Reactome Pathway:
  mitochondrial fatty acid beta-oxidation of unsaturated fatty acids (R-HSA-77288)
  Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA (R-HSA-77310)
  Beta oxidation of myristoyl-CoA to lauroyl-CoA (R-HSA-77285)
• BioCyc Pathway: MetaCyc:HS03876-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Very long chain acyl-CoA dehydrogenase deficiency	DISB7TEQ	Strong	Biomarker	[4]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[5]
Long chain acyl-CoA dehydrogenase deficiency	DISG0PIH	Disputed	Autosomal recessive	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[7]
Liver cancer	DISDE4BI	Limited	Altered Expression	[7]

12 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 Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[12]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[14]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[15]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[16]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[20]

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 Long-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADL).	[18]

References

• [1] 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.
• [2] Acyl-CoA dehydrogenase long chain expression is associated with esophageal squamous cell carcinoma progression and poor prognosis.Onco Targets Ther. 2018 Oct 31;11:7643-7653. doi: 10.2147/OTT.S171963. eCollection 2018.
• [3] PGC-1 activator-induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer.Tumori. 2020 Feb;106(1):55-63. doi: 10.1177/0300891619868287. Epub 2019 Aug 27.
• [4] Gestational, pathologic and biochemical differences between very long-chain acyl-CoA dehydrogenase deficiency and long-chain acyl-CoA dehydrogenase deficiency in the mouse. Hum Mol Genet. 2001 Sep 15;10(19):2069-77. doi: 10.1093/hmg/10.19.2069.
• [5] Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects.Hum Mol Genet. 2013 Dec 20;22(25):5249-61. doi: 10.1093/hmg/ddt382. Epub 2013 Aug 9.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression.Cell Rep. 2014 Sep 25;8(6):1930-1942. doi: 10.1016/j.celrep.2014.08.028. Epub 2014 Sep 18.
• [8] 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.
• [9] 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.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] 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.
• [12] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [13] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [16] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [17] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [18] 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.
• [19] 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.
• [20] In vitro evaluation of the hepatic lipid accumulation of bisphenol analogs: A high-content screening assay. Toxicol In Vitro. 2020 Oct;68:104959. doi: 10.1016/j.tiv.2020.104959. Epub 2020 Aug 5.