Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA1D7VL)

• DOT Name: Synaptotagmin-4 (SYT4)
• Synonyms: Synaptotagmin IV; SytIV
• Gene Name: SYT4
• Related Disease:
  Melanoma
  Obesity
  Mental disorder
  Non-insulin dependent diabetes
• UniProt ID: SYT4_HUMAN
• PDB ID: 1UGK
• Pfam ID: PF00168
• Sequence:
  MAPITTSREEFDEIPTVVGIFSAFGLVFTVSLFAWICCQRKSSKSNKTPPYKFVHVLKGV
  DIYPENLNSKKKFGADDKNEVKNKPAVPKNSLHLDLEKRDLNGNFPKTNLKPGSPSDLEN
  ATPKLFLEGEKESVSPESLKSSTSLTSEEKQEKLGTLFFSLEYNFERKAFVVNIKEARGL
  PAMDEQSMTSDPYIKMTILPEKKHKVKTRVLRKTLDPAFDETFTFYGIPYTQIQELALHF
  TILSFDRFSRDDIIGEVLIPLSGIELSEGKMLMNREIIKRNVRKSSGRGELLISLCYQST
  TNTLTVVVLKARHLPKSDVSGLSDPYVKVNLYHAKKRISKKKTHVKKCTPNAVFNELFVF
  DIPCEGLEDISVEFLVLDSERGSRNEVIGQLVLGAAAEGTGGEHWKEICDYPRRQIAKWH
  VLCDG
• Function: Synaptotagmin family member which does not bind Ca(2+). Involved in neuronal dense core vesicles (DCVs) mobility through its interaction with KIF1A. Upon increased neuronal activity, phosphorylation by MAPK8/JNK1 destabilizes the interaction with KIF1A and captures DCVs to synapses. Plays a role in dendrite formation by melanocytes.
• Tissue Specificity: Expressed in melanocytes . Expressed in brain. Within brain, expression is highest in hippocampus, with substantial levels also detected in amygdala and thalamus .

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Obesity	DIS47Y1K	Strong	Altered Expression	[2]
Mental disorder	DIS3J5R8	Limited	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Synaptotagmin-4 (SYT4).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Synaptotagmin-4 (SYT4).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Synaptotagmin-4 (SYT4).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Synaptotagmin-4 (SYT4).	[7]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Synaptotagmin-4 (SYT4).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Synaptotagmin-4 (SYT4).	[11]

2 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 decreases the methylation of Synaptotagmin-4 (SYT4).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Synaptotagmin-4 (SYT4).	[10]

References

• [1] Synaptotagmin-4 promotes dendrite extension and melanogenesis in alpaca melanocytes by regulating Ca(2+) influx via TRPM1 channels.Cell Biochem Funct. 2020 Apr;38(3):275-282. doi: 10.1002/cbf.3465. Epub 2019 Nov 19.
• [2] Age-related obesity and type 2 diabetes dysregulate neuronal associated genes and proteins in humans.Oncotarget. 2015 Oct 6;6(30):29818-32. doi: 10.18632/oncotarget.4904.
• [3] Synaptotagmin IV: biochemistry, genetics, behavior, and possible links to human psychiatric disease.Mol Neurobiol. 2001 Apr-Jun;23(2-3):173-85. doi: 10.1385/MN:23:2-3:173.
• [4] Reduced insulin secretion correlates with decreased expression of exocytotic genes in pancreatic islets from patients with type 2 diabetes.Mol Cell Endocrinol. 2012 Nov 25;364(1-2):36-45. doi: 10.1016/j.mce.2012.08.009. Epub 2012 Aug 23.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres. Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
• [9] 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.
• [10] 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.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.