Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJF0U48)

• DOT Name: Protein N-terminal asparagine amidohydrolase (NTAN1)
• Synonyms: EC 3.5.1.121; Protein NH2-terminal asparagine amidohydrolase; PNAA; Protein NH2-terminal asparagine deamidase; PNAD; Protein N-terminal Asn amidase; Protein N-terminal asparagine amidase; Protein NTN-amidase
• Gene Name: NTAN1
• Related Disease:
  Chronic kidney disease
  Chronic renal failure
  Legionnaires' disease
• UniProt ID: NTAN1_HUMAN
• PDB ID: 6A0E; 6A0F; 6A0H; 6A0I
• EC Number: 3.5.1.121
• Pfam ID: PF14736
• Sequence:
  MPLLVEGRRVRLPQSAGDLVRAHPPLEERARLLRGQSVQQVGPQGLLYVQQRELAVTSPK
  DGSISILGSDDATTCHIVVLRHTGNGATCLTHCDGTDTKAEVPLIMNSIKSFSDHAQCGR
  LEVHLVGGFSDDRQLSQKLTHQLLSEFDRQEDDIHLVTLCVTELNDREENENHFPVIYGI
  AVNIKTAEIYRASFQDRGPEEQLRAARTLAGGPMISIYDAETEQLRIGPYSWTPFPHVDF
  WLHQDDKQILENLSTSPLAEPPHFVEHIRSTLMFLKKHPSPAHTLFSGNKALLYKKNEDG
  LWEKISSPGS
• Function: N-terminal asparagine deamidase that mediates deamidation of N-terminal asparagine residues to aspartate. Required for the ubiquitin-dependent turnover of intracellular proteins that initiate with Met-Asn. These proteins are acetylated on the retained initiator methionine and can subsequently be modified by the removal of N-acetyl methionine by acylaminoacid hydrolase (AAH). Conversion of the resulting N-terminal asparagine to aspartate by NTAN1/PNAD renders the protein susceptible to arginylation, polyubiquitination and degradation as specified by the N-end rule. This enzyme does not act on substrates with internal or C-terminal asparagines and does not act on glutamine residues in any position, nor on acetylated N-terminal peptidyl Asn.
• BioCyc Pathway: MetaCyc:ENSG00000157045-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Legionnaires' disease	DIS8V4GQ	Strong	Biomarker	[2]

1 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 Protein N-terminal asparagine amidohydrolase (NTAN1).	[3]

7 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 Protein N-terminal asparagine amidohydrolase (NTAN1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein N-terminal asparagine amidohydrolase (NTAN1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein N-terminal asparagine amidohydrolase (NTAN1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein N-terminal asparagine amidohydrolase (NTAN1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein N-terminal asparagine amidohydrolase (NTAN1).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Protein N-terminal asparagine amidohydrolase (NTAN1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein N-terminal asparagine amidohydrolase (NTAN1).	[10]

References

• [1] Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.J Am Soc Nephrol. 2018 May;29(5):1513-1524. doi: 10.1681/ASN.2017101099. Epub 2018 Mar 15.
• [2] microRNA-125a-3p is regulated by MyD88 in Legionella pneumophila infection and targets NTAN1.PLoS One. 2017 Apr 26;12(4):e0176204. doi: 10.1371/journal.pone.0176204. eCollection 2017.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [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] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.