Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM3S4DE)

• DOT Name: Palmitoyl-protein thioesterase 1 (PPT1)
• Synonyms: PPT-1; EC 3.1.2.22; Palmitoyl-protein hydrolase 1
• Gene Name: PPT1
• Related Disease:
  CLN1 disease
  Neuronal ceroid lipofuscinosis
• UniProt ID: PPT1_HUMAN
• PDB ID: 3GRO
• EC Number: 3.1.2.22
• Pfam ID: PF02089
• Sequence:
  MASPGCLWLLAVALLPWTCASRALQHLDPPAPLPLVIWHGMGDSCCNPLSMGAIKKMVEK
  KIPGIYVLSLEIGKTLMEDVENSFFLNVNSQVTTVCQALAKDPKLQQGYNAMGFSQGGQF
  LRAVAQRCPSPPMINLISVGGQHQGVFGLPRCPGESSHICDFIRKTLNAGAYSKVVQERL
  VQAEYWHDPIKEDVYRNHSIFLADINQERGINESYKKNLMALKKFVMVKFLNDSIVDPVD
  SEWFGFYRSGQAKETIPLQETSLYTQDRLGLKEMDNAGQLVFLATEGDHLQLSEEWFYAH
  IIPFLG
• Function: Removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. Prefers acyl chain lengths of 14 to 18 carbons.
• KEGG Pathway:
  Fatty acid elongation (hsa00062)
  Metabolic pathways (hsa01100)
  Fatty acid metabolism (hsa01212)
  Lysosome (hsa04142)
• Reactome Pathway: Fatty acyl-CoA biosynthesis (R-HSA-75105)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CLN1 disease	DISAIONI	Definitive	Autosomal recessive	[1]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Definitive	Autosomal recessive	[1]

12 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 Palmitoyl-protein thioesterase 1 (PPT1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[7]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[8]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[9]
Orlistat	DMRJSP8	Approved	Orlistat decreases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Palmitoyl-protein thioesterase 1 (PPT1).	[13]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Palmitoyl-protein thioesterase 1 (PPT1).	[10]

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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] 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.
• [8] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [9] Orlistat Displays Antitumor Activity and Enhances the Efficacy of Paclitaxel in Human Hepatoma Hep3B Cells. Chem Res Toxicol. 2019 Feb 18;32(2):255-264. doi: 10.1021/acs.chemrestox.8b00269. Epub 2019 Jan 22.
• [10] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.