Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRUQ2N8)

• DOT Name: UbiA prenyltransferase domain-containing protein 1
• Synonyms: EC 2.5.1.-; EC 2.5.1.39; Transitional epithelial response protein 1
• Gene Name: UBIAD1
• Related Disease: Schnyder corneal dystrophy
• UniProt ID: UBIA1_HUMAN
• EC Number: 2.5.1.-; 2.5.1.39
• Pfam ID: PF01040
• Sequence:
  MAASQVLGEKINILSGETVKAGDRDPLGNDCPEQDRLPQRSWRQKCASYVLALRPWSFSA
  SLTPVALGSALAYRSHGVLDPRLLVGCAVAVLAVHGAGNLVNTYYDFSKGIDHKKSDDRT
  LVDRILEPQDVVRFGVFLYTLGCVCAACLYYLSPLKLEHLALIYFGGLSGSFLYTGGIGF
  KYVALGDLIILITFGPLAVMFAYAIQVGSLAIFPLVYAIPLALSTEAILHSNNTRDMESD
  REAGIVTLAILIGPTFSYILYNTLLFLPYLVFSILATHCTISLALPLLTIPMAFSLERQF
  RSQAFNKLPQRTAKLNLLLGLFYVFGIILAPAGSLPKI
• Function: Prenyltransferase that mediates the formation of menaquinone-4 (MK-4) and coenzyme Q10. MK-4 is a vitamin K2 isoform present at high concentrations in the brain, kidney and pancreas, and is required for endothelial cell development. Mediates the conversion of phylloquinone (PK) into MK-4, probably by cleaving the side chain of phylloquinone (PK) to release 2-methyl-1,4-naphthoquinone (menadione; K3) and then prenylating it with geranylgeranyl pyrophosphate (GGPP) to form MK-4. Also plays a role in cardiovascular development independently of MK-4 biosynthesis, by acting as a coenzyme Q10 biosynthetic enzyme: coenzyme Q10, also named ubiquinone, plays an important antioxidant role in the cardiovascular system. Mediates biosynthesis of coenzyme Q10 in the Golgi membrane, leading to protect cardiovascular tissues from NOS3/eNOS-dependent oxidative stress.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway: Metabolism of vitamin K (R-HSA-6806664)
• BioCyc Pathway: MetaCyc:ENSG00000120942-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schnyder corneal dystrophy	DISAYSN1	Definitive	Autosomal dominant	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin K	DMN6EZY	Investigative	UbiA prenyltransferase domain-containing protein 1 increases the metabolism of Vitamin K.	[12]

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 UbiA prenyltransferase domain-containing protein 1.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of UbiA prenyltransferase domain-containing protein 1.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of UbiA prenyltransferase domain-containing protein 1.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of UbiA prenyltransferase domain-containing protein 1.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of UbiA prenyltransferase domain-containing protein 1.	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of UbiA prenyltransferase domain-containing protein 1.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of UbiA prenyltransferase domain-containing protein 1.	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of UbiA prenyltransferase domain-containing protein 1.	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of UbiA prenyltransferase domain-containing protein 1.	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of UbiA prenyltransferase domain-containing protein 1.	[11]

References

• [1] Identification of the First De Novo UBIAD1 Gene Mutation Associated with Schnyder Corneal Dystrophy. J Ophthalmol. 2016;2016:1968493. doi: 10.1155/2016/1968493. Epub 2016 Jun 12.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [7] 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.
• [8] 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.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature. 2010 Nov 4;468(7320):117-21. doi: 10.1038/nature09464. Epub 2010 Oct 17.