Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3WZW8S)

• DOT Name: Malonate--CoA ligase ACSF3, mitochondrial (ACSF3)
• Synonyms: EC 6.2.1.76; Acyl-CoA synthetase family member 3
• Gene Name: ACSF3
• Related Disease:
  Combined malonic and methylmalonic acidemia
  Adult lymphoma
  B-cell neoplasm
  Inborn error of metabolism
  Lymphoma
  Malonic aciduria
  Metabolic disorder
  Methylmalonic acidemia
  Pediatric lymphoma
• UniProt ID: ACSF3_HUMAN
• EC Number: 6.2.1.76
• Pfam ID: PF00501 ; PF13193
• Sequence:
  MLPHVVLTFRRLGCALASCRLAPARHRGSGLLHTAPVARSDRSAPVFTRALAFGDRIALV
  DQHGRHTYRELYSRSLRLSQEICRLCGCVGGDLREERVSFLCANDASYVVAQWASWMSGG
  VAVPLYRKHPAAQLEYVICDSQSSVVLASQEYLELLSPVVRKLGVPLLPLTPAIYTGAVE
  EPAEVPVPEQGWRNKGAMIIYTSGTTGRPKGVLSTHQNIRAVVTGLVHKWAWTKDDVILH
  VLPLHHVHGVVNALLCPLWVGATCVMMPEFSPQQVWEKFLSSETPRINVFMAVPTIYTKL
  MEYYDRHFTQPHAQDFLRAVCEEKIRLMVSGSAALPLPVLEKWKNITGHTLLERYGMTEI
  GMALSGPLTTAVRLPGSVGTPLPGVQVRIVSENPQREACSYTIHAEGDERGTKVTPGFEE
  KEGELLVRGPSVFREYWNKPEETKSAFTLDGWFKTGDTVVFKDGQYWIRGRTSVDIIKTG
  GYKVSALEVEWHLLAHPSITDVAVIGVPDMTWGQRVTAVVTLREGHSLSHRELKEWARNV
  LAPYAVPSELVLVEEIPRNQMGKIDKKALIRHFHPS
• Function: Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester. May have some preference toward very-long-chain substrates.
• KEGG Pathway:
  Fatty acid biosynthesis (hsa00061)
  Valine, leucine and isoleucine degradation (hsa00280)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
• Reactome Pathway: Synthesis of very long-chain fatty acyl-CoAs (R-HSA-75876)
• BioCyc Pathway: MetaCyc:ENSG00000176715-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined malonic and methylmalonic acidemia	DISNSNPY	Definitive	Autosomal recessive	[1]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[2]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[2]
Inborn error of metabolism	DISO5FAY	Strong	Genetic Variation	[3]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[2]
Malonic aciduria	DIS2ST7M	Strong	Biomarker	[4]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[4]
Methylmalonic acidemia	DISHY8VB	Strong	Biomarker	[4]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[9]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Malonate--CoA ligase ACSF3, mitochondrial (ACSF3).	[11]

References

• [1] 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.
• [2] The CBFA2T3/ACSF3 locus is recurrently involved in IGH chromosomal translocation t(14;16)(q32;q24) in pediatric B-cell lymphoma with germinal center phenotype.Genes Chromosomes Cancer. 2012 Apr;51(4):338-43. doi: 10.1002/gcc.21919.
• [3] The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism.Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Nov;1864(11):1629-1643. doi: 10.1016/j.bbalip.2019.07.012. Epub 2019 Jul 31.
• [4] Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011 Aug 14;43(9):883-6. doi: 10.1038/ng.908.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] 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.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.