Details of Drug Off-Target (DOT)

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

• DOT Name: Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS)
• Synonyms: SCAD; EC 1.3.8.1; Butyryl-CoA dehydrogenase
• Gene Name: ACADS
• Related Disease:
  Advanced cancer
  Chronic kidney disease
  Chronic renal failure
  Hepatocellular carcinoma
  Short chain acyl-CoA dehydrogenase deficiency
  Acute coronary syndrome
  Bipolar disorder
  Cardiac failure
  Congestive heart failure
  Coronary atherosclerosis
  Coronary heart disease
  Epilepsy
  Erythema multiforme
  Medium chain acyl-CoA dehydrogenase deficiency
  Schizophrenia
  Neoplasm
  Pancreatic cancer
  Prader-Willi syndrome
  Myopathy
• UniProt ID: ACADS_HUMAN
• PDB ID: 2VIG; 7Y0A; 7Y0B
• EC Number: 1.3.8.1
• Pfam ID: PF00441 ; PF02770 ; PF02771
• Sequence:
  MAAALLARASGPARRALCPRAWRQLHTIYQSVELPETHQMLLQTCRDFAEKELFPIAAQV
  DKEHLFPAAQVKKMGGLGLLAMDVPEELGGAGLDYLAYAIAMEEISRGCASTGVIMSVNN
  SLYLGPILKFGSKEQKQAWVTPFTSGDKIGCFALSEPGNGSDAGAASTTARAEGDSWVLN
  GTKAWITNAWEASAAVVFASTDRALQNKGISAFLVPMPTPGLTLGKKEDKLGIRGSSTAN
  LIFEDCRIPKDSILGEPGMGFKIAMQTLDMGRIGIASQALGIAQTALDCAVNYAENRMAF
  GAPLTKLQVIQFKLADMALALESARLLTWRAAMLKDNKKPFIKEAAMAKLAASEAATAIS
  HQAIQILGGMGYVTEMPAERHYRDARITEIYEGTSEIQRLVIAGHLLRSYRS
• Function: Short-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, short-chain specific acyl-CoA dehydrogenase acts specifically on acyl-CoAs with saturated 4 to 6 carbons long primary chains.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Valine, leucine and isoleucine degradation (hsa00280)
  beta-Alanine metabolism (hsa00410)
  Propanoate metabolism (hsa00640)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway:
  Beta oxidation of butanoyl-CoA to acetyl-CoA (R-HSA-77352)
  Beta oxidation of hexanoyl-CoA to butanoyl-CoA (R-HSA-77350)
• BioCyc Pathway: MetaCyc:HS04619-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[2]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Short chain acyl-CoA dehydrogenase deficiency	DISDDRPY	Definitive	Autosomal recessive	[3]
Acute coronary syndrome	DIS7DYEW	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[7]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[7]
Epilepsy	DISBB28L	Strong	Genetic Variation	[8]
Erythema multiforme	DISKCLM1	Strong	Biomarker	[4]
Medium chain acyl-CoA dehydrogenase deficiency	DISB8C4K	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	moderate	Posttranslational Modification	[1]
Pancreatic cancer	DISJC981	moderate	Genetic Variation	[11]
Prader-Willi syndrome	DISYWMLU	moderate	Altered Expression	[12]
Myopathy	DISOWG27	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[17]
Lindane	DMB8CNL	Approved	Lindane decreases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[22]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[23]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[23]
Farnesol	DMV2X1B	Investigative	Farnesol increases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[23]
CITCO	DM0N634	Investigative	CITCO increases the expression of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS).	[20]

References

• [1] ACADS acts as a potential methylation biomarker associated with the proliferation and metastasis of hepatocellular carcinomas.Aging (Albany NY). 2019 Oct 25;11(20):8825-8844. doi: 10.18632/aging.102292. Epub 2019 Oct 25.
• [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] 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.
• [4] Difference in clinical presentations and related angiographic findings among early, late, and very late sirolimus-eluting stent failures requiring target lesion revascularization.Int J Cardiol. 2017 Sep 15;243:116-120. doi: 10.1016/j.ijcard.2017.05.052. Epub 2017 May 13.
• [5] Search for peripheral biomarkers in patients affected by acutely psychotic bipolar disorder: a proteomic approach.Mol Biosyst. 2014 Jun;10(6):1246-54. doi: 10.1039/c4mb00068d. Epub 2014 Feb 19.
• [6] [Change of short-chain acyl-CoA dehydrogenase in heart failure after myocardial infarction in rats and the intervention of aerobic exercise].Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2019 Feb;31(2):172-177. doi: 10.3760/cma.j.issn.2095-4352.2019.02.010.
• [7] Determinants and Long-Term Outcomes of Percutaneous Coronary Interventions vs. Surgery for Multivessel Disease According to Clinical Presentation.Circ J. 2018 Mar 23;82(4):1092-1100. doi: 10.1253/circj.CJ-17-1173. Epub 2018 Feb 9.
• [8] High prevalence of short-chain acyl-CoA dehydrogenase deficiency in the Netherlands, but no association with epilepsy of unknown origin in childhood.Neuropediatrics. 2011 Feb;42(1):13-7. doi: 10.1055/s-0031-1275342. Epub 2011 Apr 15.
• [9] Respiratory complex II defect in siblings associated with a symptomatic secondary block in fatty acid oxidation.J Inherit Metab Dis. 2003;26(7):659-70. doi: 10.1023/b:boli.0000005659.52200.c1.
• [10] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [11] Prediction of overall survival after re-irradiation with stereotactic body radiation therapy for pancreatic cancer with a novel prognostic model (the SCAD score).Radiother Oncol. 2018 Nov;129(2):313-318. doi: 10.1016/j.radonc.2018.08.012. Epub 2018 Sep 11.
• [12] Persistent growth failure in Prader-Willi syndrome associated with short-chain acyl-CoA dehydrogenase gene variant.J Child Neurol. 2008 Jan;23(1):112-7. doi: 10.1177/0883073807307979.
• [13] Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin.Mol Genet Metab. 2008 Feb;93(2):179-89. doi: 10.1016/j.ymgme.2007.09.021. Epub 2007 Dec 3.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Organochloride pesticides impaired mitochondrial function in hepatocytes and aggravated disorders of fatty acid metabolism. Sci Rep. 2017 Apr 11;7:46339. doi: 10.1038/srep46339.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.