Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSPV7AX)

• DOT Name: Molybdopterin synthase catalytic subunit (MOCS2)
• Synonyms: EC 2.8.1.12; MOCO1-B; Molybdenum cofactor synthesis protein 2 large subunit; Molybdenum cofactor synthesis protein 2B; MOCS2B; Molybdopterin-synthase large subunit; MPT synthase large subunit
• Gene Name: MOCS2
• Related Disease:
  Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
  Cerebral palsy
  Lung adenocarcinoma
  Molybdenum cofactor deficiency
• UniProt ID: MOC2B_HUMAN
• PDB ID: 4AP8; 5MPO
• EC Number: 2.8.1.12
• Pfam ID: PF02391
• Sequence:
  MSSLEISSSCFSLETKLPLSPPLVEDSAFEPSRKDMDEVEEKSKDVINFTAEKLSVDEVS
  QLVISPLCGAISLFVGTTRNNFEGKKVISLEYEAYLPMAENEVRKICSDIRQKWPVKHIA
  VFHRLGLVPVSEASIIIAVSSAHRAASLEAVSYAIDTLKAKVPIWKKEIYEESSTWKGNK
  ECFWASNS
• Function: Catalytic subunit of the molybdopterin synthase complex, a complex that catalyzes the conversion of precursor Z into molybdopterin. Acts by mediating the incorporation of 2 sulfur atoms from thiocarboxylated MOCS2A into precursor Z to generate a dithiolene group.
• Tissue Specificity: Highest levels are found in heart and skeletal muscle. Lower levels are present in brain, kidney and pancreas. Very low levels are found in lung and peripheral blood leukocytes.
• KEGG Pathway:
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  Sulfur relay system (hsa04122)
• Reactome Pathway: Molybdenum cofactor biosynthesis (R-HSA-947581)
• BioCyc Pathway: MetaCyc:HS09033-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B	DIS1LMIJ	Definitive	Autosomal recessive	[1]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[3]
Molybdenum cofactor deficiency	DISKS8QN	Strong	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Molybdopterin synthase catalytic subunit (MOCS2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Molybdopterin synthase catalytic subunit (MOCS2).	[14]

10 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 Molybdopterin synthase catalytic subunit (MOCS2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Molybdopterin synthase catalytic subunit (MOCS2).	[16]

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] Molybdenum cofactor deficiency mimics cerebral palsy: differentiating factors for diagnosis.Pediatr Neurol. 2012 Aug;47(2):147-9. doi: 10.1016/j.pediatrneurol.2012.04.013.
• [3] Genomic aberrations in lung adenocarcinoma in never smokers.PLoS One. 2010 Dec 6;5(12):e15145. doi: 10.1371/journal.pone.0015145.
• [4] The Clinical and Molecular Characteristics of Molybdenum Cofactor Deficiency Due to MOCS2 Mutations.Pediatr Neurol. 2019 Oct;99:55-59. doi: 10.1016/j.pediatrneurol.2019.04.021. Epub 2019 May 3.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [13] 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.
• [14] 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.
• [15] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [16] 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.