Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7S8WU0)

• DOT Name: Synaptotagmin-9 (SYT9)
• Synonyms: Synaptotagmin IX; SytIX
• Gene Name: SYT9
• Related Disease:
  Cockayne syndrome
  Cockayne syndrome type 2
  Heart septal defect
  Pancreatic cancer
  Amyotrophic lateral sclerosis
• UniProt ID: SYT9_HUMAN
• Pfam ID: PF00168
• Sequence:
  MPGARDALCHQALQLLAELCARGALEHDSCQDFIYHLRDRARPRLRDPDISVSLLTLVVT
  ACGLALFGVSLFVSWKLCWVPWRERGLPSGSKDNNQEPLNYMDTETNEQENSEDFLDPPT
  PCPDSSMKISHTSPDIPLSTQTGIQENCAHGVRVQRQVTEPTSSARHNSIRRQLNLSNPD
  FNIQQLQKQEQLTGIGRIKPELYKQRSLDNDDGRRSNSKACGKLNFILKYDCDLEQLIVK
  IHKAVNLPAKDFSGTSDPYVKIYLLPDRKTKHQTKVHRKTLNPVFDEVFLFPVPYNDLEA
  RKLHFSVYDFDRFSRHDLIGQVVVDHFLDLADFPRECILWKDIEYVTNDNVDLGELMFSL
  CYLPTAGRLTITIIKARNLKAMDITGASDPYVKVSLMCDGRRLKKRKTSTKRNTLNPVYN
  EAIVFDVPPENIDQIHLSIAVMDYDRVGHNEIIGVCQVGNEAERLGRDHWSEMLSYPRKP
  IAHWHSLVEKR
• Function: May be involved in Ca(2+)-dependent exocytosis of secretory vesicles through Ca(2+) and phospholipid binding to the C2 domain or may serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis.
• Reactome Pathway:
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cockayne syndrome	DISW6GL2	Strong	Biomarker	[1]
Cockayne syndrome type 2	DIS3X0GQ	Strong	Altered Expression	[1]
Heart septal defect	DISQ5C5J	Strong	Genetic Variation	[2]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[3]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[4]

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 Synaptotagmin-9 (SYT9).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Synaptotagmin-9 (SYT9).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Synaptotagmin-9 (SYT9).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Synaptotagmin-9 (SYT9).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Synaptotagmin-9 (SYT9).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Synaptotagmin-9 (SYT9).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Synaptotagmin-9 (SYT9).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Synaptotagmin-9 (SYT9).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Synaptotagmin-9 (SYT9).	[15]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Synaptotagmin-9 (SYT9).	[16]

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 increases the methylation of Synaptotagmin-9 (SYT9).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Synaptotagmin-9 (SYT9).	[14]

References

• [1] Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation. Cell Rep. 2016 Mar 22;14(11):2554-61. doi: 10.1016/j.celrep.2016.02.051. Epub 2016 Mar 10.
• [2] A genetic variant in a homocysteine metabolic gene that increases the risk of congenital cardiac septal defects in Han Chinese populations.IUBMB Life. 2017 Sep;69(9):700-705. doi: 10.1002/iub.1651.
• [3] Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4.Cancer Causes Control. 2013 Mar;24(3):595-602. doi: 10.1007/s10552-012-0138-0. Epub 2013 Jan 19.
• [4] Whole genome analyses reveal no pathogenetic single nucleotide or structural differences between monozygotic twins discordant for amyotrophic lateral sclerosis.Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):385-92. doi: 10.3109/21678421.2015.1040029. Epub 2015 May 11.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation. Cell Rep. 2016 Mar 22;14(11):2554-61. doi: 10.1016/j.celrep.2016.02.051. Epub 2016 Mar 10.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] 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.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] 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.
• [15] 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.
• [16] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.