Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLNA39Z)

• DOT Name: Glycylpeptide N-tetradecanoyltransferase 2 (NMT2)
• Synonyms: EC 2.3.1.97; Myristoyl-CoA:protein N-myristoyltransferase 2; NMT 2; Peptide N-myristoyltransferase 2; Protein-lysine myristoyltransferase NMT2; EC 2.3.1.-; Type II N-myristoyltransferase
• Gene Name: NMT2
• Related Disease:
  Brain neoplasm
  Hypogonadism
• UniProt ID: NMT2_HUMAN
• PDB ID: 4C2X; 6PAU
• EC Number: 2.3.1.-; 2.3.1.97
• Pfam ID: PF01233 ; PF02799
• Sequence:
  MAEDSESAASQQSLELDDQDTCGIDGDNEEETEHAKGSPGGYLGAKKKKKKQKRKKEKPN
  SGGTKSDSASDSQEIKIQQPSKNPSVPMQKLQDIQRAMELLSACQGPARNIDEAAKHRYQ
  FWDTQPVPKLDEVITSHGAIEPDKDNVRQEPYSLPQGFMWDTLDLSDAEVLKELYTLLNE
  NYVEDDDNMFRFDYSPEFLLWALRPPGWLLQWHCGVRVSSNKKLVGFISAIPANIRIYDS
  VKKMVEINFLCVHKKLRSKRVAPVLIREITRRVNLEGIFQAVYTAGVVLPKPIATCRYWH
  RSLNPRKLVEVKFSHLSRNMTLQRTMKLYRLPDVTKTSGLRPMEPKDIKSVRELINTYLK
  QFHLAPVMDEEEVAHWFLPREHIIDTFVVESPNGKLTDFLSFYTLPSTVMHHPAHKSLKA
  AYSFYNIHTETPLLDLMSDALILAKSKGFDVFNALDLMENKTFLEKLKFGIGDGNLQYYL
  YNWRCPGTDSEKVGLVLQ
• Function: Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins. Also able to mediate N-terminal lysine myristoylation of proteins: catalyzes myristoylation of ARF6 on both 'Gly-2' and 'Lys-3'. Lysine myristoylation is required to maintain ARF6 on membranes during the GTPase cycle.
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  Membrane binding and targetting of GAG proteins (R-HSA-174490)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[1]
Hypogonadism	DISICMNI	Strong	Genetic Variation	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Glycylpeptide N-tetradecanoyltransferase 2 (NMT2) affects the response to substance of Doxorubicin.	[17]
Etoposide	DMNH3PG	Approved	Glycylpeptide N-tetradecanoyltransferase 2 (NMT2) affects the response to substance of Etoposide.	[17]
Mitomycin	DMH0ZJE	Approved	Glycylpeptide N-tetradecanoyltransferase 2 (NMT2) affects the response to substance of Mitomycin.	[17]
Topotecan	DMP6G8T	Approved	Glycylpeptide N-tetradecanoyltransferase 2 (NMT2) affects the response to substance of Topotecan.	[17]

3 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 Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[12]

11 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 Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Glycylpeptide N-tetradecanoyltransferase 2 (NMT2).	[16]

References

• [1] Expression of N-myristoyltransferase in human brain tumors.Neurochem Res. 2005 Jan;30(1):9-13. doi: 10.1007/s11064-004-9680-9.
• [2] Is the disruption of an N-myristoyltransferase (NMT2) associated with hypoplastic testes?.Am J Med Genet A. 2007 Aug 1;143A(15):1796-8. doi: 10.1002/ajmg.a.31799.
• [3] 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.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] 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.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.