Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGGPR6J)

• DOT Name: Acetoacetyl-CoA synthetase (AACS)
• Synonyms: EC 6.2.1.16; Acyl-CoA synthetase family member 1; Protein sur-5 homolog
• Gene Name: AACS
• Related Disease:
  Fatty liver disease
  Non-alcoholic fatty liver disease
  Acute myelogenous leukaemia
  Neuroblastoma
  Obesity
• UniProt ID: AACS_HUMAN
• EC Number: 6.2.1.16
• Pfam ID: PF16177 ; PF00501
• Sequence:
  MSKEERPGREEILECQVMWEPDSKKNTQMDRFRAAVGAACGLALESYDDLYHWSVESYSD
  FWAEFWKFSGIVFSRVYDEVVDTSKGIADVPEWFKGSRLNYAENLLRHKENDRVALYIAR
  EGKEEIVKVTFEELRQEVALFAAAMRKMGVKKGDRVVGYLPNSEHAVEAMLAAASIGAIW
  SSTSPDFGVNGVLDRFSQIQPKLIFSVEAVVYNGKEHNHMEKLQQVVKGLPDLKKVVVIP
  YVSSRENIDLSKIPNSVFLDDFLATGTSEQAPQLEFEQLPFSHPLFIMFSSGTTGAPKCM
  VHSAGGTLIQHLKEHLLHGNMTSSDILLCYTTVGWMMWNWMVSLLATGAAMVLYDGSPLV
  PTPNVLWDLVDRIGITVLVTGAKWLSVLEEKAMKPVETHSLQMLHTILSTGSPLKAQSYE
  YVYRCIKSSILLGSISGGTDIISCFMGHNFSLPVYKGEIQARNLGMAVEAWNEEGKAVWG
  ESGELVCTKPIPCQPTHFWNDENGNKYRKAYFSKFPGIWAHGDYCRINPKTGGIVMLGRS
  DGTLNPNGVRFGSSEIYNIVESFEEVEDSLCVPQYNKYREERVILFLKMASGHAFQPDLV
  KRIRDAIRMGLSARHVPSLILETKGIPYTLNGKKVEVAVKQIIAGKAVEQGGAFSNPETL
  DLYRDIPELQGF
• Function: Converts acetoacetate to acetoacetyl-CoA in the cytosol. Ketone body-utilizing enzyme, responsible for the synthesis of cholesterol and fatty acids.
• Tissue Specificity: Highly expressed in kidney, heart and brain, but low in liver.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Synthesis of Ketone Bodies (R-HSA-77111)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Biomarker	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[2]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[3]
Obesity	DIS47Y1K	Limited	Biomarker	[4]

10 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 Acetoacetyl-CoA synthetase (AACS).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Acetoacetyl-CoA synthetase (AACS).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Acetoacetyl-CoA synthetase (AACS).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acetoacetyl-CoA synthetase (AACS).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acetoacetyl-CoA synthetase (AACS).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Acetoacetyl-CoA synthetase (AACS).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Acetoacetyl-CoA synthetase (AACS).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Acetoacetyl-CoA synthetase (AACS).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Acetoacetyl-CoA synthetase (AACS).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Acetoacetyl-CoA synthetase (AACS).	[14]

References

• [1] Identification of Potential Plasma Biomarkers for Nonalcoholic Fatty Liver Disease by Integrating Transcriptomics and Proteomics in Laying Hens.J Nutr. 2017 Mar;147(3):293-303. doi: 10.3945/jn.116.240358. Epub 2017 Jan 11.
• [2] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [3] Transcriptional regulation of acetoacetyl-CoA synthetase by Sp1 in neuroblastoma cells.Biochem Biophys Res Commun. 2018 Jan 1;495(1):652-658. doi: 10.1016/j.bbrc.2017.11.068. Epub 2017 Nov 11.
• [4] Genetic obesity affects neural ketone body utilization in the rat brain.Obesity (Silver Spring). 2009 Mar;17(3):611-5. doi: 10.1038/oby.2008.566. Epub 2008 Dec 11.
• [5] 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.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] 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.
• [10] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.