Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOV8UJM)

• DOT Name: Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3)
• Synonyms: Molybdenum cofactor synthesis protein 3; Molybdopterin synthase sulfurylase; MPT synthase sulfurylase
• Gene Name: MOCS3
• UniProt ID: MOCS3_HUMAN
• PDB ID: 3I2V
• EC Number: 2.7.7.80; 2.8.1.11
• Pfam ID: PF00581 ; PF00899
• Sequence:
  MASREEVLALQAEVAQREEELNSLKQKLASALLAEQEPQPERLVPVSPLPPKAALSRDEI
  LRYSRQLVLPELGVHGQLRLGTACVLIVGCGGLGCPLAQYLAAAGVGRLGLVDYDVVEMS
  NLARQVLHGEALAGQAKAFSAAASLRRLNSAVECVPYTQALTPATALDLVRRYDVVADCS
  DNVPTRYLVNDACVLAGRPLVSASALRFEGQITVYHYDGGPCYRCIFPQPPPAETVTNCA
  DGGVLGVVTGVLGCLQALEVLKIAAGLGPSYSGSLLLFDALRGHFRSIRLRSRRLDCAAC
  GERPTVTDLLDYEAFCGSSATDKCRSLQLLSPEERVSVTDYKRLLDSGAFHLLLDVRPQV
  EVDICRLPHALHIPLKHLERRDAESLKLLKEAIWEEKQGTQEGAAVPIYVICKLGNDSQK
  AVKILQSLSAAQELDPLTVRDVVGGLMAWAAKIDGTFPQY
• Function: Plays a central role in 2-thiolation of mcm(5)S(2)U at tRNA wobble positions of cytosolic tRNA(Lys), tRNA(Glu) and tRNA(Gln). Also essential during biosynthesis of the molybdenum cofactor. Acts by mediating the C-terminal thiocarboxylation of sulfur carriers URM1 and MOCS2A. Its N-terminus first activates URM1 and MOCS2A as acyl-adenylates (-COAMP), then the persulfide sulfur on the catalytic cysteine is transferred to URM1 and MOCS2A to form thiocarboxylation (-COSH) of their C-terminus. The reaction probably involves hydrogen sulfide that is generated from the persulfide intermediate and that acts as a nucleophile towards URM1 and MOCS2A. Subsequently, a transient disulfide bond is formed. Does not use thiosulfate as sulfur donor; NFS1 acting as a sulfur donor for thiocarboxylation reactions.
• KEGG Pathway: Sulfur relay system (hsa04122)
• Reactome Pathway: Molybdenum cofactor biosynthesis (R-HSA-947581)
• BioCyc Pathway: MetaCyc:HS04742-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[3]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[4]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Adenylyltransferase and sulfurtransferase MOCS3 (MOCS3).	[8]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.