Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT79GAY2)

• DOT Name: Protein-serine O-palmitoleoyltransferase porcupine (PORCN)
• Synonyms: EC 2.3.1.250; Protein MG61
• Gene Name: PORCN
• Related Disease:
  Focal dermal hypoplasia
  Microphthalmia, isolated, with coloboma
• UniProt ID: PORCN_HUMAN
• PDB ID: 7URA; 7URC; 7URD; 7URE
• EC Number: 2.3.1.250
• Pfam ID: PF03062
• Sequence:
  MATFSRQEFFQQLLQGCLLPTAQQGLDQIWLLLAICLACRLLWRLGLPSYLKHASTVAGG
  FFSLYHFFQLHMVWVVLLSLLCYLVLFLCRHSSHRGVFLSVTILIYLLMGEMHMVDTVTW
  HKMRGAQMIVAMKAVSLGFDLDRGEVGTVPSPVEFMGYLYFVGTIVFGPWISFHSYLQAV
  QGRPLSCRWLQKVARSLALALLCLVLSTCVGPYLFPYFIPLNGDRLLRNKKRKARGTMVR
  WLRAYESAVSFHFSNYFVGFLSEATATLAGAGFTEEKDHLEWDLTVSKPLNVELPRSMVE
  VVTSWNLPMSYWLNNYVFKNALRLGTFSAVLVTYAASALLHGFSFHLAAVLLSLAFITYV
  EHVLRKRLARILSACVLSKRCPPDCSHQHRLGLGVRALNLLFGALAIFHLAYLGSLFDVD
  VDDTTEEQGYGMAYTVHKWSELSWASHWVTFGCWIFYRLIG
• Function: Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors.
• Tissue Specificity: Isoform 1 is expressed in fetal brain, brain, amygdala, caudate nucleus, cerebellum, hippocampus, pituitary, thalamus, heart, skeletal muscle and testis. Isoform 4 is expressed in amygdala, corpus callosum, hippocampus, spinal cord, kidney, liver, lung, spleen, uterus, testis. Isoform 2 and isoform 3 are expressed in substantia negra, spinal cord, heart and lung.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  LGK974 inhibits PORCN (R-HSA-5340573)
  WNT ligand biogenesis and trafficking (R-HSA-3238698)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Focal dermal hypoplasia	DISXBAOL	Definitive	X-linked	[1]
Microphthalmia, isolated, with coloboma	DISLSEUJ	Supportive	Autosomal dominant	[2]

8 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 Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[8]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[11]

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 affects the methylation of Protein-serine O-palmitoleoyltransferase porcupine (PORCN).	[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] Non-syndromic anophthalmia/microphthalmia can be caused by a PORCN variant inherited in X-linked recessive manner. Am J Med Genet A. 2021 Jan;185(1):250-255. doi: 10.1002/ajmg.a.61938. Epub 2020 Oct 27.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression. Environ Health. 2017 Jun 14;16(1):59. doi: 10.1186/s12940-017-0267-8.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [10] 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.
• [11] 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.