Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9TMQL3)

• DOT Name: Phosphofurin acidic cluster sorting protein 1 (PACS1)
• Synonyms: PACS-1
• Gene Name: PACS1
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Neoplasm
  Schuurs-Hoeijmakers syndrome
  Bipolar depression
  Bipolar disorder
  Drug dependence
  Epilepsy
  Obesity
  Substance abuse
  Substance dependence
  Coloboma
  Constipation
  Intellectual disability
• UniProt ID: PACS1_HUMAN
• Pfam ID: PF10254
• Sequence:
  MAERGGAGGGPGGAGGGSGQRGSGVAQSPQQPPPQQQQQQPPQQPTPPKLAQATSSSSST
  SAAAASSSSSSTSTSMAVAVASGSAPPGGPGPGRTPAPVQMNLYATWEVDRSSSSCVPRL
  FSLTLKKLVMLKEMDKDLNSVVIAVKLQGSKRILRSNEIVLPASGLVETELQLTFSLQYP
  HFLKRDANKLQIMLQRRKRYKNRTILGYKTLAVGLINMAEVMQHPNEGALVLGLHSNVKD
  VSVPVAEIKIYSLSSQPIDHEGIKSKLSDRSPDIDNYSEEEEESFSSEQEGSDDPLHGQD
  LFYEDEDLRKVKKTRRKLTSTSAITRQPNIKQKFVALLKRFKVSDEVGFGLEHVSREQIR
  EVEEDLDELYDSLEMYNPSDSGPEMEETESILSTPKPKLKPFFEGMSQSSSQTEIGSLNS
  KGSLGKDTTSPMELAALEKIKSTWIKNQDDSLTETDTLEITDQDMFGDASTSLVVPEKVK
  TPMKSSKTDLQGSASPSKVEGVHTPRQKRSTPLKERQLSKPLSERTNSSDSERSPDLGHS
  TQIPRKVVYDQLNQILVSDAALPENVILVNTTDWQGQYVAELLQDQRKPVVCTCSTVEVQ
  AVLSALLTRIQRYCNCNSSMPRPVKVAAVGGQSYLSSILRFFVKSLANKTSDWLGYMRFL
  IIPLGSHPVAKYLGSVDSKYSSSFLDSGWRDLFSRSEPPVSEQLDVAGRVMQYVNGAATT
  HQLPVAEAMLTCRHKFPDEDSYQKFIPFIGVVKVGLVEDSPSTAGDGDDSPVVSLTVPST
  SPPSSSGLSRDATATPPSSPSMSSALAIVGSPNSPYGDVIGLQVDYWLGHPGERRREGDK
  RDASSKNTLKSVFRSVQVSRLPHSGEAQLSGTMAMTVVTKEKNKKVPTIFLSKKPREKEV
  DSKSQVIEGISRLICSAKQQQTMLRVSIDGVEWSDIKFFQLAAQWPTHVKHFPVGLFSGS
  KAT
• Function: Coat protein that is involved in the localization of trans-Golgi network (TGN) membrane proteins that contain acidic cluster sorting motifs. Controls the endosome-to-Golgi trafficking of furin and mannose-6-phosphate receptor by connecting the acidic-cluster-containing cytoplasmic domain of these molecules with the adapter-protein complex-1 (AP-1) of endosomal clathrin-coated membrane pits. Involved in HIV-1 nef-mediated removal of MHC-I from the cell surface to the TGN. Required for normal ER Ca2+ handling in lymphocytes. Together with WDR37, it plays an essential role in lymphocyte development, quiescence and survival. Required for stabilizing peripheral lymphocyte populations.
• Reactome Pathway: Nef mediated downregulation of MHC class I complex cell surface expression (R-HSA-164940)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Schuurs-Hoeijmakers syndrome	DISR9ELF	Definitive	Autosomal dominant	[3]
Bipolar depression	DISA75FU	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Drug dependence	DIS9IXRC	Strong	Biomarker	[5]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Obesity	DIS47Y1K	Strong	Genetic Variation	[7]
Substance abuse	DIS327VW	Strong	Biomarker	[5]
Substance dependence	DISDRAAR	Strong	Biomarker	[5]
Coloboma	DISP39N5	Limited	Genetic Variation	[8]
Constipation	DISRQXWI	Limited	Genetic Variation	[9]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphofurin acidic cluster sorting protein 1 (PACS1).	[20]

References

• [1] Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am J Hum Genet. 2012 Dec 7;91(6):1122-7. doi: 10.1016/j.ajhg.2012.10.013. Epub 2012 Nov 15.
• [2] Complementation of non-tumorigenicity of HPV18-positive cervical carcinoma cells involves differential mRNA expression of cellular genes including potential tumor suppressor genes on chromosome 11q13.Cancer Genet. 2013 Jul-Aug;206(7-8):279-92. doi: 10.1016/j.cancergen.2013.06.002. Epub 2013 Sep 14.
• [3] 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.
• [4] Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
• [5] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [6] A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.Am J Hum Genet. 2018 May 3;102(5):995-1007. doi: 10.1016/j.ajhg.2018.03.005. Epub 2018 Apr 12.
• [7] Association Study of Three Gene Polymorphisms Recently Identified by a Genome-Wide Association Study with Obesity-Related Phenotypes in Chinese Children.Obes Facts. 2017;10(3):179-190. doi: 10.1159/000471487. Epub 2017 Jun 1.
• [8] Ocular manifestations of PACS1 mutation.J AAPOS. 2018 Aug;22(4):323-325. doi: 10.1016/j.jaapos.2017.12.008. Epub 2018 Mar 14.
• [9] Schuurs-Hoeijmakers syndrome in two patients from Japan.Am J Med Genet A. 2019 Mar;179(3):341-343. doi: 10.1002/ajmg.a.9. Epub 2018 Dec 27.
• [10] Schuurs-Hoeijmakers syndrome in a patient from India.Am J Med Genet A. 2019 Apr;179(4):522-524. doi: 10.1002/ajmg.a.61058. Epub 2019 Jan 28.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] 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.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] 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.
• [19] 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.
• [20] 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.