Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH2V54F)

• DOT Name: Vacuolar fusion protein MON1 homolog A (MON1A)
• Gene Name: MON1A
• Related Disease: Iron metabolism disease
• UniProt ID: MON1A_HUMAN
• Pfam ID: PF19036 ; PF19037 ; PF19038
• Sequence:
  MHPGGGPSRAERLELGLGRERPAKAIFLHRRPGEGGGRERCLRCGHVCVRRGPGPREAVP
  SGRPRPDTLTPPWVRQRAVTGTFCASWTPLRNRRAQRMATDMQRKRSSECLDGTLTPSDG
  QSMERAESPTPGMAQGMEPGAGQEGAMFVHARSYEDLTESEDGAASGDSHKEGTRGPPPL
  PTDMRQISQDFSELSTQLTGVARDLQEEMLPGSSEDWLEPPGAVGRPATEPPREGTTEGD
  EEDATEAWRLHQKHVFVLSEAGKPVYSRYGSEEALSSTMGVMVALVSFLEADKNAIRSIH
  ADGYKVVFVRRSPLVLVAVARTRQSAQELAQELLYIYYQILSLLTGAQLSHIFQQKQNYD
  LRRLLSGSERITDNLLQLMARDPSFLMGAARCLPLAAAVRDTVSASLQQARARSLVFSIL
  LARNQLVALVRRKDQFLHPIDLHLLFNLISSSSSFREGEAWTPVCLPKFNAAGFFHAHIS
  YLEPDTDLCLLLVSTDREDFFAVSDCRRRFQERLRKRGAHLALREALRTPYYSVAQVGIP
  DLRHFLYKSKSSGLFTSPEIEAPYTSEEEQERLLGLYQYLHSRAHNASRPLKTIYYTGPN
  ENLLAWVTGAFELYMCYSPLGTKASAVSAIHKLMRWIRKEEDRLFILTPLTY
• Function: Plays an important role in membrane trafficking through the secretory apparatus. Not involved in endocytic trafficking to lysosomes. Acts in concert with CCZ1, as a guanine exchange factor (GEF) for RAB7, promotes the exchange of GDP to GTP, converting it from an inactive GDP-bound form into an active GTP-bound form.
• KEGG Pathway: Mitophagy - animal (hsa04137)
• Reactome Pathway: RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Iron metabolism disease	DISWDM9J	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Vacuolar fusion protein MON1 homolog A (MON1A).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Vacuolar fusion protein MON1 homolog A (MON1A).	[10]

References

• [1] Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice.Nat Genet. 2007 Aug;39(8):1025-32. doi: 10.1038/ng2059. Epub 2007 Jul 15.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] 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.