Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBE2LTI)

• DOT Name: Alpha-tubulin N-acetyltransferase 1 (ATAT1)
• Synonyms: Alpha-TAT; Alpha-TAT1; TAT; EC 2.3.1.108; Acetyltransferase mec-17 homolog
• Gene Name: ATAT1
• UniProt ID: ATAT_HUMAN
• PDB ID: 3VWD; 3VWE; 4B5O; 4B5P; 4GS4; 4IF5; 4PK2; 4PK3; 4U9Y; 4U9Z
• EC Number: 2.3.1.108
• Pfam ID: PF05301
• Sequence:
  MEFPFDVDALFPERITVLDQHLRPPARRPGTTTPARVDLQQQIMTIIDELGKASAKAQNL
  SAPITSASRMQSNRHVVYILKDSSARPAGKGAIIGFIKVGYKKLFVLDDREAHNEVEPLC
  ILDFYIHESVQRHGHGRELFQYMLQKERVEPHQLAIDRPSQKLLKFLNKHYNLETTVPQV
  NNFVIFEGFFAHQHRPPAPSLRATRHSRAAAVDPTPAAPARKLPPKRAEGDIKPYSSSDR
  EFLKVAVEPPWPLNRAPRRATPPAHPPPRSSSLGNSPERGPLRPFVPEQELLRSLRLCPP
  HPTARLLLAADPGGSPAQRRRTRGTPPGLVAQSCCYSRHGGVNSSSPNTGNQDSKQGEQE
  TKNRSASEEQALSQDGSGEKPMHTAPPQAPAPPAQSWTVGGDILNARFIRNLQERRSTRP
  W
• Function: Specifically acetylates 'Lys-40' in alpha-tubulin on the lumenal side of microtubules. Promotes microtubule destabilization and accelerates microtubule dynamics; this activity may be independent of acetylation activity. Acetylates alpha-tubulin with a slow enzymatic rate, due to a catalytic site that is not optimized for acetyl transfer. Enters the microtubule through each end and diffuses quickly throughout the lumen of microtubules. Acetylates only long/old microtubules because of its slow acetylation rate since it does not have time to act on dynamically unstable microtubules before the enzyme is released. Required for normal sperm flagellar function. Promotes directional cell locomotion and chemotaxis, through AP2A2-dependent acetylation of alpha-tubulin at clathrin-coated pits that are concentrated at the leading edge of migrating cells. May facilitate primary cilium assembly.
• Reactome Pathway: Cilium Assembly (R-HSA-5617833)
• BioCyc Pathway: MetaCyc:ENSG00000137343-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[4]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[9]

1 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 Alpha-tubulin N-acetyltransferase 1 (ATAT1).	[6]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [6] 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.
• [7] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [9] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.