Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO65AE3)

• DOT Name: Hyccin (HYCC1)
• Synonyms: Down-regulated by CTNNB1 protein A
• Gene Name: HYCC1
• Related Disease: Hypomyelinating leukodystrophy 5
• UniProt ID: HYCCI_HUMAN
• PDB ID: 5DSE; 6BQ1
• Pfam ID: PF09790
• Sequence:
  MFTSEKGVVEEWLSEFKTLPETSLPNYATNLKDKSSLVSSLYKVIQEPQSELLEPVCHQL
  FEFYRSGEEQLLQFTLQFLPELIWCYLAVSASRNVHSSGCIEALLLGVYNLEIVDKQGHT
  KVLSFTIPSLSKPSVYHEPSSIGSMALTESALSQHGLSKVVYSGPHPQREMLTAQNRFEV
  LTFLLLCYNAALTYMPSVSLQSLCQICSRICVCGYPRQHVRKYKGISSRIPVSSGFMVQM
  LTGIYFAFYNGEWDLAQKALDDIIYRAQLELYPEPLLVANAIKASLPHGPMKSNKEGTRC
  IQVEITPTSSRISRNAVTSMSIRGHRWKRHGNTELTGQEELMEISEVDEGFYSRAASSTS
  QSGLSNSSHNCSNKPSIGKNHRRSGGSKTGGKEKETTGESCKDHFARKQTQRAQSENLEL
  LSLKRLTLTTSQSLPKPSSHGLAKTAATVFSKSFEQVSGVTVPHNPSSAVGCGAGTDANR
  FSACSLQEEKLIYVSERTELPMKHQSGQQRPPSISITLSTD
• Function: Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane. The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis. HYCC1 plays a key role in oligodendrocytes formation, a cell type with expanded plasma membrane that requires generation of PtdIns(4)P. Its role in oligodendrocytes formation probably explains its importance in myelination of the central and peripheral nervous system. May also have a role in the beta-catenin/Lef signaling pathway (Probable).
• Tissue Specificity: Widely expressed. Highest levels in heart, brain, placenta, spleen and testis.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypomyelinating leukodystrophy 5	DISSCOVT	Definitive	Autosomal recessive	[1]

10 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 Hyccin (HYCC1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hyccin (HYCC1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hyccin (HYCC1).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Hyccin (HYCC1).	[5]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Hyccin (HYCC1).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Hyccin (HYCC1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Hyccin (HYCC1).	[9]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Hyccin (HYCC1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Hyccin (HYCC1).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Hyccin (HYCC1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Hyccin (HYCC1).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Hyccin (HYCC1).	[10]

References

• [1] A deletion in DRCTNNB1A associated with hypomyelination and juvenile onset cataract. Eur J Hum Genet. 2008 Feb;16(2):261-4. doi: 10.1038/sj.ejhg.5201935. Epub 2007 Oct 10.
• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [6] 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.
• [7] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [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.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.