Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX8T7F6)

• DOT Name: 2-phosphoxylose phosphatase 1 (PXYLP1)
• Synonyms: EC 3.1.3.-; Acid phosphatase-like protein 2; Xylosyl phosphatase; epididymis luminal protein 124
• Gene Name: PXYLP1
• UniProt ID: PXYP1_HUMAN
• EC Number: 3.1.3.-
• Pfam ID: PF00328
• Sequence:
  MLFRNRFLLLLALAALLAFVSLSLQFFHLIPVSTPKNGMSSKSRKRIMPDPVTEPPVTDP
  VYEALLYCNIPSVAERSMEGHAPHHFKLVSVHVFIRHGDRYPLYVIPKTKRPEIDCTLVA
  NRKPYHPKLEAFISHMSKGSGASFESPLNSLPLYPNHPLCEMGELTQTGVVQHLQNGQLL
  RDIYLKKHKLLPNDWSADQLYLETTGKSRTLQSGLALLYGFLPDFDWKKIYFRHQPSALF
  CSGSCYCPVRNQYLEKEQRRQYLLRLKNSQLEKTYGEMAKIVDVPTKQLRAANPIDSMLC
  HFCHNVSFPCTRNGCVDMEHFKVIKTHQIEDERERREKKLYFGYSLLGAHPILNQTIGRM
  QRATEGRKEELFALYSAHDVTLSPVLSALGLSEARFPRFAARLIFELWQDREKPSEHSVR
  ILYNGVDVTFHTSFCQDHHKRSPKPMCPLENLVRFVKRDMFVALGGSGTNYYDACHREGF
• Function: Responsible for the 2-O-dephosphorylation of xylose in the glycosaminoglycan-protein linkage region of proteoglycans thereby regulating the amount of mature glycosaminoglycan (GAG) chains. Sulfated glycosaminoglycans (GAGs), including heparan sulfate and chondroitin sulfate, are synthesized on the so-called common GAG-protein linkage region (GlcUAbeta1-3Galbeta1-3Galbeta1-4Xylbeta1-O-Ser) of core proteins, which is formed by the stepwise addition of monosaccharide residues by the respective specific glycosyltransferases. Xylose 2-O-dephosphorylation during completion of linkage region formation is a prerequisite for the initiation and efficient elongation of the repeating disaccharide region of GAG chains.
• Tissue Specificity: Widely expressed. Strongly expressed in spleen, fetal liver, moderately in placenta, pancreas, kidney, thymus and colon.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of 2-phosphoxylose phosphatase 1 (PXYLP1).	[1]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of 2-phosphoxylose phosphatase 1 (PXYLP1).	[15]

15 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 2-phosphoxylose phosphatase 1 (PXYLP1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[8]
Menadione	DMSJDTY	Approved	Menadione affects the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 2-phosphoxylose phosphatase 1 (PXYLP1).	[16]

References

• [1] 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.
• [2] 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.
• [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] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] 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.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.