Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTED0W1S)

• DOT Name: Acyl-coenzyme A diphosphatase FITM2 (FITM2)
• Synonyms: EC 3.6.1.-; Fat storage-inducing transmembrane protein 2; Fat-inducing protein 2
• Gene Name: FITM2
• Related Disease:
  Siddiqi syndrome
  Deafness dystonia syndrome
  Lipodystrophy
  Non-syndromic ichthyosis
  Peripheral sensory neuropathies
• UniProt ID: FITM2_HUMAN
• EC Number: 3.6.1.-
• Pfam ID: PF10261
• Sequence:
  MEHLERCEWLLRGTLVRAAVRRYLPWALVASMLAGSLLKELSPLPESYLSNKRNVLNVYF
  VKVAWAWTFCLLLPFIALTNYHLTGKAGLVLRRLSTLLVGTAIWYICTSIFSNIEHYTGS
  CYQSPALEGVRKEHQSKQQCHQEGGFWHGFDISGHSFLLTFCALMIVEEMSVLHEVKTDR
  SHCLHTAITTLVVALGILTFIWVLMFLCTAVYFHNLSQKVFGTLFGLLSWYGTYGFWYPK
  AFSPGLPPQSCSLNLKQDSYKK
• Function: Fatty acyl-coenzyme A (CoA) diphosphatase that hydrolyzes fatty acyl-CoA to yield acyl-4'-phosphopantetheine and adenosine 3',5'-bisphosphate. Preferentially hydrolyzes unsaturated long-chain acyl-CoA substrates such as oleoyl-CoA/(9Z)-octadecenoyl-CoA and arachidonoyl-CoA/(5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA in the endoplasmic reticulum (ER) lumen. This catalytic activity is required for maintaining ER structure and for lipid droplets (LDs) biogenesis, which are lipid storage organelles involved in maintaining lipid and energy homeostasis. Directly binds to diacylglycerol (DAGs) and triacylglycerol, which is also important for LD biogenesis. May support directional budding of nacent LDs from the ER into the cytosol by reducing DAG levels at sites of LD formation. Plays a role in the regulation of cell morphology and cytoskeletal organization.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Lipid particle organization (R-HSA-8964572)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Siddiqi syndrome	DISR56LG	Definitive	Autosomal recessive	[1]
Deafness dystonia syndrome	DIS0480U	Strong	Genetic Variation	[2]
Lipodystrophy	DIS3SGVD	Strong	Biomarker	[2]
Non-syndromic ichthyosis	DISZ9QBQ	Strong	Genetic Variation	[2]
Peripheral sensory neuropathies	DISYWI6M	Strong	Genetic Variation	[2]

11 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 Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Acyl-coenzyme A diphosphatase FITM2 (FITM2).	[12]

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] A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy. Dis Model Mech. 2017 Feb 1;10(2):105-118. doi: 10.1242/dmm.026476. Epub 2016 Dec 15.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [10] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [11] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.