Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ZTZH0)

• DOT Name: Vesicle-associated membrane protein-associated protein B/C
• Synonyms: VAMP-B/VAMP-C; VAMP-associated protein B/C; VAP-B/VAP-C
• Gene Name: VAPB
• Related Disease:
  Amyotrophic lateral sclerosis type 8
  Adult-onset proximal spinal muscular atrophy, autosomal dominant
  Amyotrophic lateral sclerosis
• UniProt ID: VAPB_HUMAN
• PDB ID: 2MDK; 3IKK
• Pfam ID: PF00635
• Sequence:
  MAKVEQVLSLEPQHELKFRGPFTDVVTTNLKLGNPTDRNVCFKVKTTAPRRYCVRPNSGI
  IDAGASINVSVMLQPFDYDPNEKSKHKFMVQSMFAPTDTSDMEAVWKEAKPEDLMDSKLR
  CVFELPAENDKPHDVEINKIISTTASKTETPIVSKSLSSSLDDTEVKKVMEECKRLQGEV
  QRLREENKQFKEEDGLRMRKTVQSNSPISALAPTGKEEGLSTRLLALVVLFFIVGVIIGK
  IAL
• Function: Endoplasmic reticulum (ER)-anchored protein that mediates the formation of contact sites between the ER and endosomes via interaction with FFAT motif-containing proteins such as STARD3 or WDR44. Interacts with STARD3 in a FFAT motif phosphorylation dependent manner. Via interaction with WDR44 participates in neosynthesized protein export. Participates in the endoplasmic reticulum unfolded protein response (UPR) by inducing ERN1/IRE1 activity. Involved in cellular calcium homeostasis regulation.
• Tissue Specificity: Ubiquitous. Isoform 1 predominates.
• KEGG Pathway:
  Cholesterol metabolism (hsa04979)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  RHOC GTPase cycle (R-HSA-9013106)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOG GTPase cycle (R-HSA-9013408)
  Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 8	DISA3XPU	Definitive	Autosomal dominant	[1]
Adult-onset proximal spinal muscular atrophy, autosomal dominant	DISMC6D7	Supportive	Autosomal dominant	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[3]

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 Vesicle-associated membrane protein-associated protein B/C.	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Vesicle-associated membrane protein-associated protein B/C.	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Vesicle-associated membrane protein-associated protein B/C.	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Vesicle-associated membrane protein-associated protein B/C.	[8]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Vesicle-associated membrane protein-associated protein B/C.	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Vesicle-associated membrane protein-associated protein B/C.	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Vesicle-associated membrane protein-associated protein B/C.	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Vesicle-associated membrane protein-associated protein B/C.	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Vesicle-associated membrane protein-associated protein B/C.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin affects the phosphorylation of Vesicle-associated membrane protein-associated protein B/C.	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Vesicle-associated membrane protein-associated protein B/C.	[6]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004 Nov;75(5):822-31. doi: 10.1086/425287. Epub 2004 Sep 15.
• [3] Amyotrophic Lateral Sclerosis Overview. 2001 Mar 23 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] 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.
• [5] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] 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.
• [7] 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.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] 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.
• [10] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.