Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1TS9M9)

• DOT Name: Acyl-coenzyme A synthetase ACSM1, mitochondrial (ACSM1)
• Synonyms: EC 6.2.1.2; Acyl-CoA synthetase medium-chain family member 1; Benzoate--CoA ligase; EC 6.2.1.25; Butyrate--CoA ligase 1; Butyryl-coenzyme A synthetase 1; Lipoate-activating enzyme; Middle-chain acyl-CoA synthetase 1; Xenobiotic/medium-chain fatty acid-CoA ligase HXM-B
• Gene Name: ACSM1
• Related Disease:
  Carcinoma
  Essential hypertension
  Lung cancer
  Lung neoplasm
  Major depressive disorder
  Schizophrenia
  Cerebral palsy
• UniProt ID: ACSM1_HUMAN
• EC Number: 6.2.1.2; 6.2.1.25
• Pfam ID: PF00501 ; PF13193
• Sequence:
  MQWLMRFRTLWGIHKSFHNIHPAPSQLRCRSLSEFGAPRWNDYEVPEEFNFASYVLDYWA
  QKEKEGKRGPNPAFWWVNGQGDEVKWSFREMGDLTRRVANVFTQTCGLQQGDHLALMLPR
  VPEWWLVAVGCMRTGIIFIPATILLKAKDILYRLQLSKAKGIVTIDALASEVDSIASQCP
  SLKTKLLVSDHSREGWLDFRSLVKSASPEHTCVKSKTLDPMVIFFTSGTTGFPKMAKHSH
  GLALQPSFPGSRKLRSLKTSDVSWCLSDSGWIVATIWTLVEPWTAGCTVFIHHLPQFDTK
  VIIQTLLKYPINHFWGVSSIYRMILQQDFTSIRFPALEHCYTGGEVVLPKDQEEWKRRTG
  LLLYENYGQSETGLICATYWGMKIKPGFMGKATPPYDVQVIDDKGSILPPNTEGNIGIRI
  KPVRPVSLFMCYEGDPEKTAKVECGDFYNTGDRGKMDEEGYICFLGRSDDIINASGYRIG
  PAEVESALVEHPAVAESAVVGSPDPIRGEVVKAFIVLTPQFLSHDKDQLTKELQQHVKSV
  TAPYKYPRKVEFVSELPKTITGKIERKELRKKETGQM
• Function: Catalyzes the activation of fatty acids by CoA to produce an acyl-CoA, the first step in fatty acid metabolism. Capable of activating medium-chain fatty acids (e.g. butyric (C4) to decanoic (C10) acids), and certain carboxylate-containing xenobiotics, e.g. benzoate. Also catalyzes the activation of lipoate to lipoyl-nucleoside monophosphate. Activates lipoate with GTP at a 1000-fold higher rate than with ATP and activates both (R)- and (S)-lipoate to the respective lipoyl-GMP, with a preference for (R)-lipoate.
• KEGG Pathway:
  Butanoate metabolism (hsa00650)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Conjugation of phenylacetate with glutamine (R-HSA-177162)
  Conjugation of benzoate with glycine (R-HSA-177135)
• BioCyc Pathway: MetaCyc:HS09445-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Strong	Biomarker	[1]
Essential hypertension	DIS7WI98	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung neoplasm	DISVARNB	Strong	Biomarker	[3]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[4]
Cerebral palsy	DIS82ODL	Limited	Genetic Variation	[5]

4 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 synthetase ACSM1, mitochondrial (ACSM1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Acyl-coenzyme A synthetase ACSM1, mitochondrial (ACSM1).	[7]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Acyl-coenzyme A synthetase ACSM1, mitochondrial (ACSM1).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Acyl-coenzyme A synthetase ACSM1, mitochondrial (ACSM1).	[8]

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 Acyl-coenzyme A synthetase ACSM1, mitochondrial (ACSM1).	[9]

References

• [1] New network topology approaches reveal differential correlation patterns in breast cancer.BMC Syst Biol. 2013 Aug 15;7:78. doi: 10.1186/1752-0509-7-78.
• [2] Two medium-chain acyl-coenzyme A synthetase genes, SAH and MACS1, are associated with plasma high-density lipoprotein cholesterol levels, but they are not associated with essential hypertension.J Hypertens. 2004 Oct;22(10):1903-7. doi: 10.1097/00004872-200410000-00012.
• [3] A comparison of transcriptomic and metabonomic technologies for identifying biomarkers predictive of two-year rodent cancer bioassays.Toxicol Sci. 2007 Mar;96(1):40-6. doi: 10.1093/toxsci/kfl171. Epub 2006 Nov 17.
• [4] Genetic association of ACSM1 variation with schizophrenia and major depressive disorder in the Han Chinese population.Am J Med Genet B Neuropsychiatr Genet. 2015 Mar;168B(2):144-9. doi: 10.1002/ajmg.b.32291. Epub 2015 Feb 5.
• [5] Evidence of Construct Validity for the Modified Mental Fatigue Scale When Used in Persons with Cerebral Palsy.Dev Neurorehabil. 2020 May;23(4):240-252. doi: 10.1080/17518423.2019.1645227. Epub 2019 Aug 12.
• [6] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [7] 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.
• [8] 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.
• [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.