Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYFT67L)

• DOT Name: Xaa-Pro aminopeptidase 3
• Synonyms: X-Pro aminopeptidase 3; EC 3.4.11.9; Aminopeptidase P3; APP3
• Gene Name: XPNPEP3
• Related Disease:
  Nephronophthisis-like nephropathy 1
  Late-onset nephronophthisis
• UniProt ID: XPP3_HUMAN
• PDB ID: 5X49
• EC Number: 3.4.11.9
• Pfam ID: PF05195 ; PF00557
• Sequence:
  MPWLLSAPKLVPAVANVRGLSGCMLCSQRRYSLQPVPERRIPNRYLGQPSPFTHPHLLRP
  GEVTPGLSQVEYALRRHKLMSLIQKEAQGQSGTDQTVVVLSNPTYYMSNDIPYTFHQDNN
  FLYLCGFQEPDSILVLQSLPGKQLPSHKAILFVPRRDPSRELWDGPRSGTDGAIALTGVD
  EAYTLEEFQHLLPKMKAETNMVWYDWMRPSHAQLHSDYMQPLTEAKAKSKNKVRGVQQLI
  QRLRLIKSPAEIERMQIAGKLTSQAFIETMFTSKAPVEEAFLYAKFEFECRARGADILAY
  PPVVAGGNRSNTLHYVKNNQLIKDGEMVLLDGGCESSCYVSDITRTWPVNGRFTAPQAEL
  YEAVLEIQRDCLALCFPGTSLENIYSMMLTLIGQKLKDLGIMKNIKENNAFKAARKYCPH
  HVGHYLGMDVHDTPDMPRSLPLQPGMVITIEPGIYIPEDDKDAPEKFRGLGVRIEDDVVV
  TQDSPLILSADCPKEMNDIEQICSQAS
• Function: Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Leu-Pro-Ala. Also shows low activity towards peptides with Ala or Ser at the P1 position ; [Isoform 1]: Promotes TNFRSF1B-mediated phosphorylation of MAPK8/JNK1 and MAPK9/JNK2, suggesting a function as an adapter protein for TNFRSF1B; the effect is independent of XPNPEP3 peptidase activity. May inhibit apoptotic cell death induced via TNF-TNFRSF1B signaling.
• Tissue Specificity: Isoform 1 and isoform 2 are widely expressed, with isoform 1 being more abundant.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephronophthisis-like nephropathy 1	DIS5H9NS	Strong	Autosomal recessive	[1]
Late-onset nephronophthisis	DIS8G9LN	Supportive	Autosomal recessive	[1]

12 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 Xaa-Pro aminopeptidase 3.	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Xaa-Pro aminopeptidase 3.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Xaa-Pro aminopeptidase 3.	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Xaa-Pro aminopeptidase 3.	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Xaa-Pro aminopeptidase 3.	[6]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Xaa-Pro aminopeptidase 3.	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Xaa-Pro aminopeptidase 3.	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Xaa-Pro aminopeptidase 3.	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Xaa-Pro aminopeptidase 3.	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Xaa-Pro aminopeptidase 3.	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Xaa-Pro aminopeptidase 3.	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Xaa-Pro aminopeptidase 3.	[13]

References

• [1] Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J Clin Invest. 2010 Mar;120(3):791-802. doi: 10.1172/JCI40076. Epub 2010 Feb 22.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] 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.
• [6] 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.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [9] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [10] 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.
• [11] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [12] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [13] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.