Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3KGDEE)

• DOT Name: Aspartyl/asparaginyl beta-hydroxylase (ASPH)
• Synonyms: EC 1.14.11.16; Aspartate beta-hydroxylase; ASP beta-hydroxylase; Peptide-aspartate beta-dioxygenase
• Gene Name: ASPH
• Related Disease: Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome
• UniProt ID: ASPH_HUMAN
• PDB ID: 5APA; 5JQY; 5JTC; 5JZ6; 5JZ8; 5JZA; 5JZU; 6Q9F; 6Q9I; 6QA5; 6RK9; 6YYU; 6YYV; 6YYW; 6YYX; 6YYY; 6Z6Q; 6Z6R; 7BMI; 7BMJ; 7E6J; 7YB8; 7YB9; 7YBA; 7YBB; 7YBC
• EC Number: 1.14.11.16
• Pfam ID: PF05279 ; PF05118 ; PF13432
• Sequence:
  MAQRKNAKSSGNSSSSGSGSGSTSAGSSSPGARRETKHGGHKNGRKGGLSGTSFFTWFMV
  IALLGVWTSVAVVWFDLVDYEEVLGKLGIYDADGDGDFDVDDAKVLLGLKERSTSEPAVP
  PEEAEPHTEPEEQVPVEAEPQNIEDEAKEQIQSLLHEMVHAEHVEGEDLQQEDGPTGEPQ
  QEDDEFLMATDVDDRFETLEPEVSHEETEHSYHVEETVSQDCNQDMEEMMSEQENPDSSE
  PVVEDERLHHDTDDVTYQVYEEQAVYEPLENEGIEITEVTAPPEDNPVEDSQVIVEEVSI
  FPVEEQQEVPPETNRKTDDPEQKAKVKKKKPKLLNKFDKTIKAELDAAEKLRKRGKIEEA
  VNAFKELVRKYPQSPRARYGKAQCEDDLAEKRRSNEVLRGAIETYQEVASLPDVPADLLK
  LSLKRRSDRQQFLGHMRGSLLTLQRLVQLFPNDTSLKNDLGVGYLLIGDNDNAKKVYEEV
  LSVTPNDGFAKVHYGFILKAQNKIAESIPYLKEGIESGDPGTDDGRFYFHLGDAMQRVGN
  KEAYKWYELGHKRGHFASVWQRSLYNVNGLKAQPWWTPKETGYTELVKSLERNWKLIRDE
  GLAVMDKAKGLFLPEDENLREKGDWSQFTLWQQGRRNENACKGAPKTCTLLEKFPETTGC
  RRGQIKYSIMHPGTHVWPHTGPTNCRLRMHLGLVIPKEGCKIRCANETKTWEEGKVLIFD
  DSFEHEVWQDASSFRLIFIVDVWHPELTPQQRRSLPAI
• Function: [Isoform 1]: Specifically hydroxylates an Asp or Asn residue in certain epidermal growth factor-like (EGF) domains of a number of proteins; [Isoform 8]: Membrane-bound Ca(2+)-sensing protein, which is a structural component of the ER-plasma membrane junctions. Isoform 8 regulates the activity of Ca(+2) released-activated Ca(+2) (CRAC) channels in T-cells.
• Tissue Specificity: Isoform 1 is detected in all tissues tested. Isoform 8 is mainly expressed in pancreas, heart, brain, kidney and liver. Isoform 8 is expressed in kidney (at protein level).
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Cardiac muscle contraction (hsa04260)
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Protein hydroxylation (R-HSA-9629569)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome	DISDKWMD	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Aspartyl/asparaginyl beta-hydroxylase (ASPH) decreases the response to substance of Arsenic trioxide.	[25]
Warfarin	DMJYCVW	Approved	Aspartyl/asparaginyl beta-hydroxylase (ASPH) affects the response to substance of Warfarin.	[26]

3 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 Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[14]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[14]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[14]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[14]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[22]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[23]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the expression of Aspartyl/asparaginyl beta-hydroxylase (ASPH).	[24]

References

• [1] Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome. Am J Hum Genet. 2014 May 1;94(5):755-9. doi: 10.1016/j.ajhg.2014.04.002. Epub 2014 Apr 24.
• [2] 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.
• [3] 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.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] 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.
• [10] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] 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.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [15] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [16] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] 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.
• [23] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [24] Analysis of lead toxicity in human cells. BMC Genomics. 2012 Jul 27;13:344.
• [25] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [26] Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy. Pharmacogenomics. 2016 Aug;17(13):1425-39. doi: 10.2217/pgs-2016-0061. Epub 2016 Aug 4.