Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOWN2K9)

• DOT Name: S-methyl-5'-thioadenosine phosphorylase (MTAP)
• Synonyms: EC 2.4.2.28; 5'-methylthioadenosine phosphorylase; MTA phosphorylase; MTAP; MTAPase
• Gene Name: MTAP
• Related Disease: Diaphyseal medullary stenosis-bone malignancy syndrome
• UniProt ID: MTAP_HUMAN
• PDB ID: 1CB0; 1CG6; 1K27; 1SD1; 1SD2; 3LN5; 3OZC; 3OZD; 3OZE; 5EUB; 5TC5; 5TC6; 5TC7; 5TC8; 6DYZ; 6DZ0; 6DZ2; 6DZ3
• EC Number: 2.4.2.28
• Pfam ID: PF01048
• Sequence:
  MASGTTTTAVKIGIIGGTGLDDPEILEGRTEKYVDTPFGKPSDALILGKIKNVDCVLLAR
  HGRQHTIMPSKVNYQANIWALKEEGCTHVIVTTACGSLREEIQPGDIVIIDQFIDRTTMR
  PQSFYDGSHSCARGVCHIPMAEPFCPKTREVLIETAKKLGLRCHSKGTMVTIEGPRFSSR
  AESFMFRTWGADVINMTTVPEVVLAKEAGICYASIAMATDYDCWKEHEEAVSVDRVLKTL
  KENANKAKSLLLTTIPQIGSTEWSETLHNLKNMAQFSVLLPRH
• Function: Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Has broad substrate specificity with 6-aminopurine nucleosides as preferred substrates.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Methionine salvage pathway (R-HSA-1237112)
• BioCyc Pathway: MetaCyc:HS01913-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diaphyseal medullary stenosis-bone malignancy syndrome	DISEY9EM	Strong	Autosomal dominant	[1]

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 S-methyl-5'-thioadenosine phosphorylase (MTAP).	[2]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[15]

14 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 S-methyl-5'-thioadenosine phosphorylase (MTAP).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of S-methyl-5'-thioadenosine phosphorylase (MTAP).	[13]

References

• [1] Genetic profiling differentiates second primary tumors from metastases in adult metachronous soft tissue sarcoma. Sarcoma. 2008;2008:431019. doi: 10.1155/2008/431019. Epub 2009 Feb 2.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] 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.
• [7] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [8] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [9] 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.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.