Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6C1WQD)

• DOT Name: Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1)
• Synonyms: EC 6.2.1.1; Acetate--CoA ligase 2; Acetyl-CoA synthetase 2; AceCS2; Acyl-CoA synthetase short-chain family member 1; Propionate--CoA ligase; EC 6.2.1.17
• Gene Name: ACSS1
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Hepatocellular carcinoma
  Myocardial infarction
  Narcolepsy
  Neoplasm
  Non-small-cell lung cancer
  Polyp of large intestine
  Precancerous condition
  Renal cell carcinoma
  Bladder cancer
  Clear cell renal carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Melanoma
• UniProt ID: ACS2L_HUMAN
• PDB ID: 3GLR; 3GLT; 3GLU; 4BVE; 4BVF; 4BVG; 4C78; 5Y4H; 5YTK
• EC Number: 6.2.1.1; 6.2.1.17
• Pfam ID: PF16177 ; PF00501 ; PF13193
• Sequence:
  MAARTLGRGVGRLLGSLRGLSGQPARPPCGVSAPRRAASGPSGSAPAVAAAAAQPGSYPA
  LSAQAAREPAAFWGPLARDTLVWDTPYHTVWDCDFSTGKIGWFLGGQLNVSVNCLDQHVR
  KSPESVALIWERDEPGTEVRITYRELLETTCRLANTLKRHGVHRGDRVAIYMPVSPLAVA
  AMLACARIGAVHTVIFAGFSAESLAGRINDAKCKVVITFNQGLRGGRVVELKKIVDEAVK
  HCPTVQHVLVAHRTDNKVHMGDLDVPLEQEMAKEDPVCAPESMGSEDMLFMLYTSGSTGM
  PKGIVHTQAGYLLYAALTHKLVFDHQPGDIFGCVADIGWITGHSYVVYGPLCNGATSVLF
  ESTPVYPNAGRYWETVERLKINQFYGAPTAVRLLLKYGDAWVKKYDRSSLRTLGSVGEPI
  NCEAWEWLHRVVGDSRCTLVDTWWQTETGGICIAPRPSEEGAEILPAMAMRPFFGIVPVL
  MDEKGSVVEGSNVSGALCISQAWPGMARTIYGDHQRFVDAYFKAYPGYYFTGDGAYRTEG
  GYYQITGRMDDVINISGHRLGTAEIEDAIADHPAVPESAVIGYPHDIKGEAAFAFIVVKD
  SAGDSDVVVQELKSMVATKIAKYAVPDEILVVKRLPKTRSGKVMRRLLRKIITSEAQELG
  DTTTLEDPSIIAEILSVYQKCKDKQAAAK
• Function: Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids. Acetate is the preferred substrate. Can also utilize propionate with a much lower affinity. Provides acetyl-CoA that is utilized mainly for oxidation under ketogenic conditions. Involved in thermogenesis under ketogenic conditions, using acetate as a vital fuel when carbohydrate availability is insufficient.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Pyruvate metabolism (hsa00620)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
• Reactome Pathway: Ethanol oxidation (R-HSA-71384)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[3]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Polyp of large intestine	DISRE1MK	Strong	Altered Expression	[1]
Precancerous condition	DISV06FL	Strong	Altered Expression	[1]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[7]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[6]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[7]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[7]
Melanoma	DIS1RRCY	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[14]
Sodium acetate anhydrous	DMH21E0	Approved	Sodium acetate anhydrous increases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[20]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[15]

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 Acetyl-coenzyme A synthetase 2-like, mitochondrial (ACSS1).	[17]

References

• [1] Downregulation of acetyl-CoA synthetase 2 is a metabolic hallmark of tumor progression and aggressiveness in colorectal carcinoma.Mod Pathol. 2017 Feb;30(2):267-277. doi: 10.1038/modpathol.2016.172. Epub 2016 Oct 7.
• [2] Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization.Cell Rep. 2015 Dec 1;13(9):2014-26. doi: 10.1016/j.celrep.2015.10.045. Epub 2015 Nov 19.
• [3] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [4] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [5] Prognostic Impact of Metabolism Reprogramming Markers Acetyl-CoA Synthetase 2 Phosphorylation and Ketohexokinase-A Expression in Non-Small-Cell Lung Carcinoma.Front Oncol. 2019 Nov 5;9:1123. doi: 10.3389/fonc.2019.01123. eCollection 2019.
• [6] Acetyl-CoA synthetase 2 enhances tumorigenesis and is indicative of a poor prognosis for patients with renal cell carcinoma.Urol Oncol. 2018 May;36(5):243.e9-243.e20. doi: 10.1016/j.urolonc.2018.01.013. Epub 2018 Mar 2.
• [7] Reprogrammed lipid metabolism in bladder cancer with cisplatin resistance.Oncotarget. 2018 Jan 13;9(17):13231-13243. doi: 10.18632/oncotarget.24229. eCollection 2018 Mar 2.
• [8] Glucose-independent Acetate Metabolism Promotes Melanoma Cell Survival and Tumor Growth.J Biol Chem. 2016 Oct 14;291(42):21869-21879. doi: 10.1074/jbc.M115.712166. Epub 2016 Aug 18.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Transcriptional Regulation of Human Arylamine N-Acetyltransferase 2 Gene by Glucose and Insulin in Liver Cancer Cell Lines. Toxicol Sci. 2022 Nov 23;190(2):158-172. doi: 10.1093/toxsci/kfac103.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.