Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUPCT1V)

• DOT Name: Gap junction alpha-4 protein (GJA4)
• Synonyms: Connexin-37; Cx37
• Gene Name: GJA4
• UniProt ID: CXA4_HUMAN
• Pfam ID: PF00029
• Sequence:
  MGDWGFLEKLLDQVQEHSTVVGKIWLTVLFIFRILILGLAGESVWGDEQSDFECNTAQPG
  CTNVCYDQAFPISHIRYWVLQFLFVSTPTLVYLGHVIYLSRREERLRQKEGELRALPAKD
  PQVERALAAVERQMAKISVAEDGRLRIRGALMGTYVASVLCKSVLEAGFLYGQWRLYGWT
  MEPVFVCQRAPCPYLVDCFVSRPTEKTIFIIFMLVVGLISLVLNLLELVHLLCRCLSRGM
  RARQGQDAPPTQGTSSDPYTDQVFFYLPVGQGPSSPPCPTYNGLSSSEQNWANLTTEERL
  ASSRPPLFLDPPPQNGQKPPSRPSSSASKKQYV
• Function: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
• Tissue Specificity: Expressed in multiple organs and tissues, including heart, uterus, ovary, and blood vessel endothelium.
• Reactome Pathway: Gap junction assembly (R-HSA-190861)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Gap junction alpha-4 protein (GJA4).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Gap junction alpha-4 protein (GJA4).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gap junction alpha-4 protein (GJA4).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gap junction alpha-4 protein (GJA4).	[2]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Gap junction alpha-4 protein (GJA4).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Gap junction alpha-4 protein (GJA4).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Gap junction alpha-4 protein (GJA4).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Gap junction alpha-4 protein (GJA4).	[7]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Gap junction alpha-4 protein (GJA4).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Gap junction alpha-4 protein (GJA4).	[5]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Gap junction alpha-4 protein (GJA4).	[9]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Gap junction alpha-4 protein (GJA4).	[11]

References

• [1] 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.
• [2] 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.
• [3] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [4] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [9] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [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] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.