Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLLL15N)

• DOT Name: Palmitoyltransferase ZDHHC20
• Synonyms: EC 2.3.1.225; Acyltransferase ZDHHC20; EC 2.3.1.-; DHHC domain-containing cysteine-rich protein 20; DHHC20; Zinc finger DHHC domain-containing protein 20
• Gene Name: ZDHHC20
• UniProt ID: ZDH20_HUMAN
• PDB ID: 6BML; 6BMM; 6BMN; 7KHM
• EC Number: 2.3.1.-; 2.3.1.225
• Pfam ID: PF01529
• Sequence:
  MAPWTLWRCCQRVVGWVPVLFITFVVVWSYYAYVVELCVFTIFGNEENGKTVVYLVAFHL
  FFVMFVWSYWMTIFTSPASPSKEFYLSNSEKERYEKEFSQERQQEILRRAARALPIYTTS
  ASKTIRYCEKCQLIKPDRAHHCSACDSCILKMDHHCPWVNNCVGFSNYKFFLLFLLYSLL
  YCLFVAATVLEYFIKFWTNELTDTRAKFHVLFLFFVSAMFFISVLSLFSYHCWLVGKNRT
  TIESFRAPTFSYGPDGNGFSLGCSKNWRQVFGDEKKYWLLPIFSSLGDGCSFPTRLVGMD
  PEQASVTNQNEYARSSGSNQPFPIKPLSESKNRLLDSESQWLENGAEEGIVKSGTNNHVT
  VAIEN
• Function: Palmitoyltransferase that could catalyze the addition of palmitate onto various protein substrates. Catalyzes palmitoylation of Cys residues in the cytoplasmic C-terminus of EGFR, and modulates the duration of EGFR signaling by modulating palmitoylation-dependent EGFR internalization and degradation. Has a preference for acyl-CoA with C16 fatty acid chains. Can also utilize acyl-CoA with C14 and C18 fatty acid chains ; (Microbial infection) Dominant palmitoyltransferase responsible for lipidation of SARS coronavirus-2/SARS-CoV-2 spike protein. Through a sequential action with ZDHHC9, rapidly and efficiently palmitoylates spike protein following its synthesis in the endoplasmic reticulum (ER). In the infected cell, promotes spike biogenesis by protecting it from premature ER degradation, increases half-life and controls the lipid organization of its immediate membrane environment. Once the virus has formed, spike palmitoylation controls fusion with the target cell.
• Reactome Pathway: Maturation of spike protein (R-HSA-9694548)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	Palmitoyltransferase ZDHHC20 increases the Metabolic disorder ADR of Chlorothiazide.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin affects the expression of Palmitoyltransferase ZDHHC20.	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Palmitoyltransferase ZDHHC20.	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Palmitoyltransferase ZDHHC20.	[3]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Palmitoyltransferase ZDHHC20.	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Palmitoyltransferase ZDHHC20.	[5]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Palmitoyltransferase ZDHHC20.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Palmitoyltransferase ZDHHC20.	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Palmitoyltransferase ZDHHC20.	[7]

References

• [1] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [5] 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.
• [6] 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.
• [7] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [8] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [9] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.