Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNDI7YK)

• DOT Name: Methionine aminopeptidase 2 (METAP2)
• Synonyms: MAP 2; MetAP 2; EC 3.4.11.18; Initiation factor 2-associated 67 kDa glycoprotein; p67; p67eIF2; Peptidase M
• Gene Name: METAP2
• UniProt ID: MAP2_HUMAN
• PDB ID: 1B59 ; 1B6A ; 1BN5 ; 1BOA ; 1KQ0 ; 1KQ9 ; 1QZY ; 1R58 ; 1R5G ; 1R5H ; 1YW7 ; 1YW8 ; 1YW9 ; 2ADU ; 2EA2 ; 2EA4 ; 2GA2 ; 2OAZ ; 5CLS ; 5D6E ; 5D6F ; 5JFR ; 5JHU ; 5JI6 ; 5LYW ; 5LYX ; 6QED ; 6QEF ; 6QEG ; 6QEH ; 6QEI ; 6QEJ ; 7A12 ; 7A13 ; 7A14 ; 7A15 ; 7A16
• EC Number: 3.4.11.18
• Pfam ID: PF00557
• Sequence:
  MAGVEEVAASGSHLNGDLDPDDREEGAASTAEEAAKKKRRKKKKSKGPSAAGEQEPDKES
  GASVDEVARQLERSALEDKERDEDDEDGDGDGDGATGKKKKKKKKKRGPKVQTDPPSVPI
  CDLYPNGVFPKGQECEYPPTQDGRTAAWRTTSEEKKALDQASEEIWNDFREAAEAHRQVR
  KYVMSWIKPGMTMIEICEKLEDCSRKLIKENGLNAGLAFPTGCSLNNCAAHYTPNAGDTT
  VLQYDDICKIDFGTHISGRIIDCAFTVTFNPKYDTLLKAVKDATNTGIKCAGIDVRLCDV
  GEAIQEVMESYEVEIDGKTYQVKPIRNLNGHSIGQYRIHAGKTVPIVKGGEATRMEEGEV
  YAIETFGSTGKGVVHDDMECSHYMKNFDVGHVPIRLPRTKHLLNVINENFGTLAFCRRWL
  DRLGESKYLMALKNLCDLGIVDPYPPLCDIKGSYTAQFEHTILLRPTCKEVVSRGDDY
• Function: Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo.; Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis.
• Reactome Pathway: Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
• BioCyc Pathway: MetaCyc:HS03371-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Methionine aminopeptidase 2 (METAP2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Methionine aminopeptidase 2 (METAP2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methionine aminopeptidase 2 (METAP2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methionine aminopeptidase 2 (METAP2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methionine aminopeptidase 2 (METAP2).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Methionine aminopeptidase 2 (METAP2).	[6]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Methionine aminopeptidase 2 (METAP2).	[7]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Methionine aminopeptidase 2 (METAP2).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Methionine aminopeptidase 2 (METAP2).	[7]
PMID27998201-Compound-22	DMS9QA7	Patented	PMID27998201-Compound-22 decreases the activity of Methionine aminopeptidase 2 (METAP2).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methionine aminopeptidase 2 (METAP2).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Methionine aminopeptidase 2 (METAP2).	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Methionine aminopeptidase 2 (METAP2).	[14]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Methionine aminopeptidase 2 (METAP2).	[15]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Methionine aminopeptidase 2 (METAP2).	[16]
ETHIONINE	DMGESUH	Investigative	ETHIONINE decreases the activity of Methionine aminopeptidase 2 (METAP2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Methionine aminopeptidase 2 (METAP2).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Methionine aminopeptidase 2 (METAP2).	[12]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [5] 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.
• [6] 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.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [9] Effect of nitroxoline on angiogenesis and growth of human bladder cancer. J Natl Cancer Inst. 2010 Dec 15;102(24):1855-73. doi: 10.1093/jnci/djq457. Epub 2010 Nov 18.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] 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.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [14] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [15] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [16] Cancer-related proteins in serum are altered in workers occupationally exposed to polycyclic aromatic hydrocarbons: a cross-sectional study. Carcinogenesis. 2019 Jul 6;40(6):771-781. doi: 10.1093/carcin/bgz022.
• [17] Physiologically relevant metal cofactor for methionine aminopeptidase-2 is manganese. Biochemistry. 2003 May 6;42(17):5035-42. doi: 10.1021/bi020670c.