Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZMT6XV)

• DOT Name: Palmitoyltransferase ZDHHC5
• Synonyms: EC 2.3.1.225; Zinc finger DHHC domain-containing protein 5; DHHC-5; Zinc finger protein 375
• Gene Name: ZDHHC5
• Related Disease: Schizophrenia
• UniProt ID: ZDHC5_HUMAN
• EC Number: 2.3.1.225
• Pfam ID: PF01529
• Sequence:
  MPAESGKRFKPSKYVPVSAAAIFLVGATTLFFAFTCPGLSLYVSPAVPIYNAIMFLFVLA
  NFSMATFMDPGIFPRAEEDEDKEDDFRAPLYKTVEIKGIQVRMKWCATCRFYRPPRCSHC
  SVCDNCVEEFDHHCPWVNNCIGRRNYRYFFLFLLSLTAHIMGVFGFGLLYVLYHIEELSG
  VRTAVTMAVMCVAGLFFIPVAGLTGFHVVLVARGRTTNEQVTGKFRGGVNPFTNGCCNNV
  SRVLCSSPAPRYLGRPKKEKTIVIRPPFLRPEVSDGQITVKIMDNGIQGELRRTKSKGSL
  EITESQSADAEPPPPPKPDLSRYTGLRTHLGLATNEDSSLLAKDSPPTPTMYKYRPGYSS
  SSTSAAMPHSSSAKLSRGDSLKEPTSIAESSRHPSYRSEPSLEPESFRSPTFGKSFHFDP
  LSSGSRSSSLKSAQGTGFELGQLQSIRSEGTTSTSYKSLANQTRNGSLSYDSLLTPSDSP
  DFESVQAGPEPDPPLGYTSPFLSARLAQQREAERHPRLVPTGPTHREPSPVRYDNLSRHI
  VASLQEREKLLRQSPPLPGREEEPGLGDSGIQSTPGSGHAPRTSSSSDDSKRSPLGKTPL
  GRPAVPRFGKPDGLRGRGVGSPEPGPTAPYLGRSMSYSSQKAQPGVSETEEVALQPLLTP
  KDEVQLKTTYSKSNGQPKSLGSASPGPGQPPLSSPTRGGVKKVSGVGGTTYEISV
• Function: Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates such as CTNND2, CD36, NOD1, NOD2, STAT3 and S1PR1 thus plays a role in various biological processes including cell adhesion, fatty acid uptake, bacterial sensing or cardiac functions. Plays an important role in the regulation of synapse efficacy by mediating palmitoylation of delta-catenin/CTNND2, thereby increasing synaptic delivery and surface stabilization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Under basal conditions, remains at the synaptic membrane through FYN-mediated phosphorylation that prevents association with endocytic proteins. Neuronal activity enhances the internalization and trafficking of DHHC5 from spines to dendritic shafts where it palmitoylates delta-catenin/CTNND2. Regulates cell adhesion at the plasma membrane by palmitoylating GOLGA7B and DSG2. Plays a role in innate immune response by mediating the palmitoylation of NOD1 and NOD2 and their proper recruitment to the bacterial entry site and phagosomes. Participates also in fatty acid uptake by palmitoylating CD36 and thereby targeting it to the plasma membrane. Upon binding of fatty acids to CD36, gets phosphorylated by LYN leading to inactivation and subsequent CD36 caveolar endocytosis. Controls oligodendrocyte development by catalyzing STAT3 palmitoylation.
• Reactome Pathway: Maturation of spike protein (R-HSA-9694548)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Limited	Unknown	[1]

6 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 Palmitoyltransferase ZDHHC5.	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Palmitoyltransferase ZDHHC5.	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Palmitoyltransferase ZDHHC5.	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Palmitoyltransferase ZDHHC5.	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Palmitoyltransferase ZDHHC5.	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Palmitoyltransferase ZDHHC5.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Palmitoyltransferase ZDHHC5.	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Palmitoyltransferase ZDHHC5.	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Palmitoyltransferase ZDHHC5.	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Palmitoyltransferase ZDHHC5.	[10]

References

• [1] Integrating genome-wide association study and expression quantitative trait locus study identifies multiple genes and gene sets associated with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:50-54. doi: 10.1016/j.pnpbp.2017.10.003. Epub 2017 Oct 9.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.