Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCT1D53)

• DOT Name: Palmitoyltransferase ZDHHC15
• Synonyms: EC 2.3.1.225; Acyltransferase ZDHHC15; EC 2.3.1.-; Zinc finger DHHC domain-containing protein 15; DHHC-15
• Gene Name: ZDHHC15
• Related Disease:
  X-linked complex neurodevelopmental disorder
  Intellectual disability, X-linked 91
• UniProt ID: ZDH15_HUMAN
• EC Number: 2.3.1.-; 2.3.1.225
• Pfam ID: PF01529
• Sequence:
  MRRGWKMALSGGLRCCRRVLSWVPVLVIVLVVLWSYYAYVFELCLVTVLSPAEKVIYLIL
  YHAIFVFFTWTYWKSIFTLPQQPNQKFHLSYTDKERYENEERPEVQKQMLVDMAKKLPVY
  TRTGSGAVRFCDRCHLIKPDRCHHCSVCAMCVLKMDHHCPWVNNCIGFSNYKFFLQFLAY
  SVLYCLYIATTVFSYFIKYWRGELPSVRSKFHVLFLLFVACMFFVSLVILFGYHCWLVSR
  NKTTLEAFCTPVFTSGPEKNGFNLGFIKNIQQVFGDKKKFWLIPIGSSPGDGHSFPMRSM
  NESQNPLLANEETWEDNEDDNQDYPEGSSSLAVETET
• Function: Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates. Has no stringent fatty acid selectivity and in addition to palmitate can also transfer onto target proteins myristate from tetradecanoyl-CoA and stearate from octadecanoyl-CoA. Palmitoylates IGF2R and SORT1, promoting their partitioning to an endosomal membrane subdomain where they can interact with the retromer cargo-selective complex. Thereby, regulates retrograde transport from endosomes to the Golgi apparatus of these lysosomal sorting receptors and plays a role in trafficking of lysosomal proteins. In the nervous system, catalyzes the palmitoylation of DLG4/PSD95 and regulates its synaptic clustering and function in synaptogenesis. Could be involved in the differentiation of dopaminergic neurons and the development of the diencephalon. Could also catalyze the palmitoylation of GAP43. Could also palmitoylate DNAJC5 and regulate its localization to the Golgi membrane. Could also palmitoylate FYN as shown in vitro.
• Tissue Specificity: Expressed in placenta, liver, lung, kidney, heart and brain.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked complex neurodevelopmental disorder	DISI3QE9	Disputed	X-linked	[1]
Intellectual disability, X-linked 91	DISVSHJD	Limited	Unknown	[2]

4 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 ZDHHC15.	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Palmitoyltransferase ZDHHC15.	[4]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of Palmitoyltransferase ZDHHC15.	[5]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Palmitoyltransferase ZDHHC15.	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Palmitoyltransferase ZDHHC15.	[7]

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] Mutation in ZDHHC15 Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability. Neurol Genet. 2021 Jul 29;7(4):e602. doi: 10.1212/NXG.0000000000000602. eCollection 2021 Aug.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [5] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [6] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [7] 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.