Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZVRM40)

• DOT Name: S-acyl fatty acid synthase thioesterase, medium chain (OLAH)
• Synonyms: EC 3.1.2.14; Augmented in rheumatoid arthritis 1; AURA1; Oleoyl-ACP hydrolase; Thioesterase 2; TE2; Thioesterase II; Thioesterase domain-containing protein 1
• Gene Name: OLAH
• Related Disease: Migraine disorder
• UniProt ID: SAST_HUMAN
• PDB ID: 4XJV
• EC Number: 3.1.2.14
• Pfam ID: PF00975
• Sequence:
  MERGDQPKRTRNENIFNCLYKNPEATFKLICFPWMGGGSTHFAKWGQDTHDLLEVHSLRL
  PGRESRVEEPLENDISQLVDEVVCALQPVIQDKPFAFFGHSMGSYIAFRTALGLKENNQP
  EPLHLFLSSATPVHSKAWHRIPKDDELSEEQISHYLMEFGGTPKHFAEAKEFVKQCSPII
  RADLNIVRSCTSNVPSKAVLSCDLTCFVGSEDIAKDMEAWKDVTSGNAKIYQLPGGHFYL
  LDPANEKLIKNYIIKCLEVSSISNF
• Function: Contributes to the release of free fatty acids from fatty acid synthase (FASN). Has broad substrate specificity, giving rise to a range of free fatty acids with chain lengths between 10 and 16 carbon atoms (C10 - C16).
• Tissue Specificity: Detected both in lactating and non-lactating breast epithelium (at protein level) . Isoform 2 is up-regulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients .
• KEGG Pathway:
  Fatty acid biosynthesis (hsa00061)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Fatty acyl-CoA biosynthesis (R-HSA-75105)
• BioCyc Pathway: MetaCyc:HS07821-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Migraine disorder	DISFCQTG	Disputed	Genetic Variation	[1]

3 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 S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[8]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of S-acyl fatty acid synthase thioesterase, medium chain (OLAH).	[12]

References

• [1] Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine.Brain. 2019 Jul 1;142(7):1894-1904. doi: 10.1093/brain/awz134.
• [2] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [3] 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.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] 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.
• [9] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [10] 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.
• [11] 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.
• [12] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.