Details of Drug Off-Target (DOT)

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

• DOT Name: S-adenosylmethionine sensor upstream of mTORC1 (BMT2)
• Synonyms: Probable methyltransferase BMT2 homolog; EC 2.1.1.-
• Gene Name: BMT2
• UniProt ID: SAMTR_HUMAN
• EC Number: 2.1.1.-
• Pfam ID: PF11968
• Sequence:
  MEPGAGGRNTARAQRAGSPNTPPPREQERKLEQEKLSGVVKSVHRRLRKKYREVGDFDKI
  WREHCEDEETLCEYAVAMKNLADNHWAKTCEGEGRIEWCCSVCREYFQNGGKRKALEKDE
  KRAVLATKTTPALNMHESSQLEGHLTNLSFTNPEFITELLQASGKIRLLDVGSCFNPFLK
  FEEFLTVGIDIVPAVESVYKCDFLNLQLQQPLQLAQDAIDAFLKQLKNPIDSLPGELFHV
  VVFSLLLSYFPSPYQRWICCKKAHELLVLNGLLLIITPDSSHQNRHAMMMKSWKIAIESL
  GFKRFKYSKFSHMHLMAFRKISLKTTSDLVSRNYPGMLYIPQDFNSIEDEEYSNPSCYVR
  SDIEDEQLAYGFTELPDAPYDSDSGESQASSIPFYELEDPILLLS
• Function: S-adenosyl-L-methionine-binding protein that acts as an inhibitor of mTORC1 signaling via interaction with the GATOR1 and KICSTOR complexes. Acts as a sensor of S-adenosyl-L-methionine to signal methionine sufficiency to mTORC1: in presence of methionine, binds S-adenosyl-L-methionine, leading to disrupt interaction with the GATOR1 and KICSTOR complexes and promote mTORC1 signaling. Upon methionine starvation, S-adenosyl-L-methionine levels are reduced, thereby promoting the association with GATOR1 and KICSTOR, leading to inhibit mTORC1 signaling. Probably also acts as a S-adenosyl-L-methionine-dependent methyltransferase (Potential).
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

10 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 S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[4]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[5]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of S-adenosylmethionine sensor upstream of mTORC1 (BMT2).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [5] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.