Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT42GQ3D)

• DOT Name: Glycylpeptide N-tetradecanoyltransferase 1 (NMT1)
• Synonyms: EC 2.3.1.97; Myristoyl-CoA:protein N-myristoyltransferase 1; HsNMT1; NMT 1; Type I N-myristoyltransferase; Peptide N-myristoyltransferase 1; Protein-lysine myristoyltransferase NMT1; EC 2.3.1.-
• Gene Name: NMT1
• Related Disease:
  Nervous system disease
  Amelogenesis imperfecta type 1G
  Brain neoplasm
  Cardiovascular disease
  Colonic neoplasm
  Melanoma
  Rheumatoid arthritis
  Squamous cell carcinoma
  Synovitis
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
• UniProt ID: NMT1_HUMAN
• PDB ID: 1RXT ; 3IU1 ; 3IU2 ; 3IWE ; 3JTK ; 4C2Y ; 4C2Z ; 5MU6 ; 5NPQ ; 5O6H ; 5O6J ; 5O9S ; 5O9T ; 5O9U ; 5O9V ; 5UUT ; 6EHJ ; 6F56 ; 6FZ2 ; 6FZ3 ; 6FZ5 ; 6PAV ; 6QRM ; 6SJZ ; 6SK2 ; 6SK3 ; 6SK8 ; 6SKJ ; 7OWM ; 7OWN ; 7OWO ; 7OWP ; 7OWQ ; 7OWR ; 7OWU ; 7RK3
• EC Number: 2.3.1.-; 2.3.1.97
• Pfam ID: PF01233 ; PF02799
• Sequence:
  MADESETAVKPPAPPLPQMMEGNGNGHEHCSDCENEEDNSYNRGGLSPANDTGAKKKKKK
  QKKKKEKGSETDSAQDQPVKMNSLPAERIQEIQKAIELFSVGQGPAKTMEEASKRSYQFW
  DTQPVPKLGEVVNTHGPVEPDKDNIRQEPYTLPQGFTWDALDLGDRGVLKELYTLLNENY
  VEDDDNMFRFDYSPEFLLWALRPPGWLPQWHCGVRVVSSRKLVGFISAIPANIHIYDTEK
  KMVEINFLCVHKKLRSKRVAPVLIREITRRVHLEGIFQAVYTAGVVLPKPVGTCRYWHRS
  LNPRKLIEVKFSHLSRNMTMQRTMKLYRLPETPKTAGLRPMETKDIPVVHQLLTRYLKQF
  HLTPVMSQEEVEHWFYPQENIIDTFVVENANGEVTDFLSFYTLPSTIMNHPTHKSLKAAY
  SFYNVHTQTPLLDLMSDALVLAKMKGFDVFNALDLMENKTFLEKLKFGIGDGNLQYYLYN
  WKCPSMGAEKVGLVLQ
• 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.
• Tissue Specificity: Heart, gut, kidney, liver and placenta.
• Reactome Pathway:
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  Activation, myristolyation of BID and translocation to mitochondria (R-HSA-75108)
  Late Phase of HIV Life Cycle (R-HSA-162599)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Amelogenesis imperfecta type 1G	DISS8U5Q	Strong	Altered Expression	[2]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Altered Expression	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[8]
Synovitis	DISW2GPY	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[9]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Desloratadine	DM56YN7	Approved	Glycylpeptide N-tetradecanoyltransferase 1 (NMT1) affects the response to substance of Desloratadine.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Glycylpeptide N-tetradecanoyltransferase 1 (NMT1).	[20]

References

• [1] "Crimes against the Nervous System": Neurological References During the Nuremberg Doctors' Trials.World Neurosurg. 2019 Feb;122:63-70. doi: 10.1016/j.wneu.2018.10.092. Epub 2018 Oct 25.
• [2] Tanshinone II A Affects Diabetic Peripheral Neuropathic Pain via Spinal Dorsal Horn Neuronal Circuitry by Modulating Endoplasmic Reticulum Stress Pathways.Exp Clin Endocrinol Diabetes. 2020 Jan;128(1):59-65. doi: 10.1055/a-0919-4614. Epub 2019 Jul 11.
• [3] Expression of N-myristoyltransferase in human brain tumors.Neurochem Res. 2005 Jan;30(1):9-13. doi: 10.1007/s11064-004-9680-9.
• [4] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [5] N-myristoyltransferase: a potential novel diagnostic marker for colon cancer.J Transl Med. 2007 Nov 16;5:58. doi: 10.1186/1479-5876-5-58.
• [6] Palladium based nanoparticles for the treatment of advanced melanoma.Sci Rep. 2019 Mar 1;9(1):3255. doi: 10.1038/s41598-019-40258-6.
• [7] N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation.Nat Immunol. 2019 Mar;20(3):313-325. doi: 10.1038/s41590-018-0296-7. Epub 2019 Feb 4.
• [8] Elevated N-myristoyltransferase activity and expression in oral squamous cell carcinoma.Oncol Rep. 2007 Jul;18(1):93-7.
• [9] Blocking Myristoylation of Src Inhibits Its Kinase Activity and Suppresses Prostate Cancer Progression.Cancer Res. 2017 Dec 15;77(24):6950-6962. doi: 10.1158/0008-5472.CAN-17-0981. Epub 2017 Oct 16.
• [10] Investigation of Novel Regulation of N-myristoyltransferase by Mammalian Target of Rapamycin in Breast Cancer Cells.Sci Rep. 2018 Aug 28;8(1):12969. doi: 10.1038/s41598-018-30447-0.
• [11] Increased expression of N-myristoyltransferase in gallbladder carcinomas.Cancer. 2000 May 1;88(9):1992-9.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] 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.
• [16] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [17] 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.
• [18] 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.
• [19] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [20] 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.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [22] Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression. Signal Transduct Target Ther. 2023 Jan 9;8(1):14. doi: 10.1038/s41392-022-01248-9.