Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHZT92J)

• DOT Name: Palmitoyltransferase ZDHHC9
• Synonyms: EC 2.3.1.225; Zinc finger DHHC domain-containing protein 9; DHHC-9; DHHC9; Zinc finger protein 379; Zinc finger protein 380
• Gene Name: ZDHHC9
• Related Disease:
  Syndromic X-linked intellectual disability Raymond type
  X-linked intellectual disability with marfanoid habitus
• UniProt ID: ZDHC9_HUMAN
• PDB ID: 8HF3
• EC Number: 2.3.1.225
• Pfam ID: PF01529
• Sequence:
  MSVMVVRKKVTRKWEKLPGRNTFCCDGRVMMARQKGIFYLTLFLILGTCTLFFAFECRYL
  AVQLSPAIPVFAAMLFLFSMATLLRTSFSDPGVIPRALPDEAAFIEMEIEATNGAVPQGQ
  RPPPRIKNFQINNQIVKLKYCYTCKIFRPPRASHCSICDNCVERFDHHCPWVGNCVGKRN
  YRYFYLFILSLSLLTIYVFAFNIVYVALKSLKIGFLETLKETPGTVLEVLICFFTLWSVV
  GLTGFHTFLVALNQTTNEDIKGSWTGKNRVQNPYSHGNIVKNCCEVLCGPLPPSVLDRRG
  ILPLEESGSRPPSTQETSSSLLPQSPAPTEHLNSNEMPEDSSTPEEMPPPEPPEPPQEAA
  EAEK
• Function: Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, HRAS, NRAS and CGAS. The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS. May have a palmitoyltransferase activity toward the beta-2 adrenergic receptor/ADRB2 and therefore regulate G protein-coupled receptor signaling. Acts as a regulator of innate immunity by catalyzing palmitoylation of CGAS, thereby promoting CGAS homodimerization and cyclic GMP-AMP synthase activity ; (Microbial infection) Through a sequential action with ZDHHC20, rapidly and efficiently palmitoylates SARS coronavirus-2/SARS-CoV-2 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.
• Tissue Specificity: Highly expressed in kidney, skeletal muscle, brain, lung and liver. Absent in thymus, spleen and leukocytes.
• Reactome Pathway:
  Maturation of spike protein (R-HSA-9694548)
  RAS processing (R-HSA-9648002)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Syndromic X-linked intellectual disability Raymond type	DISXI0AF	Definitive	X-linked	[1]
X-linked intellectual disability with marfanoid habitus	DISEL7RK	Supportive	X-linked	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Palmitoyltransferase ZDHHC9.	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Palmitoyltransferase ZDHHC9.	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Palmitoyltransferase ZDHHC9.	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Palmitoyltransferase ZDHHC9.	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Palmitoyltransferase ZDHHC9.	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Palmitoyltransferase ZDHHC9.	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Palmitoyltransferase ZDHHC9.	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Palmitoyltransferase ZDHHC9.	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Palmitoyltransferase ZDHHC9.	[11]

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] Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability. Clin Genet. 2013 Dec;84(6):507-21. doi: 10.1111/cge.12094. Epub 2013 Mar 18.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [6] 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.
• [7] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [8] 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.
• [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] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.