Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP45YKX)

• DOT Name: Prolyl 4-hydroxylase subunit alpha-2 (P4HA2)
• Synonyms: 4-PH alpha-2; EC 1.14.11.2; Procollagen-proline,2-oxoglutarate-4-dioxygenase subunit alpha-2
• Gene Name: P4HA2
• Related Disease: Myopia 25, autosomal dominant
• UniProt ID: P4HA2_HUMAN
• PDB ID: 6EVL; 6EVM; 6EVN; 6EVO; 6EVP; 7ZSC
• EC Number: 1.14.11.2
• Pfam ID: PF13640 ; PF08336
• Sequence:
  MKLWVSALLMAWFGVLSCVQAEFFTSIGHMTDLIYAEKELVQSLKEYILVEEAKLSKIKS
  WANKMEALTSKSAADAEGYLAHPVNAYKLVKRLNTDWPALEDLVLQDSAAGFIANLSVQR
  QFFPTDEDEIGAAKALMRLQDTYRLDPGTISRGELPGTKYQAMLSVDDCFGMGRSAYNEG
  DYYHTVLWMEQVLKQLDAGEEATTTKSQVLDYLSYAVFQLGDLHRALELTRRLLSLDPSH
  ERAGGNLRYFEQLLEEEREKTLTNQTEAELATPEGIYERPVDYLPERDVYESLCRGEGVK
  LTPRRQKRLFCRYHHGNRAPQLLIAPFKEEDEWDSPHIVRYYDVMSDEEIERIKEIAKPK
  LARATVRDPKTGVLTVASYRVSKSSWLEEDDDPVVARVNRRMQHITGLTVKTAELLQVAN
  YGVGGQYEPHFDFSRNDERDTFKHLGTGNRVATFLNYMSDVEAGGATVFPDLGAAIWPKK
  GTAVFWYNLLRSGEGDYRTRHAACPVLVGCKWVSNKWFHERGQEFLRPCGSTEVD
• Function: Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.
• Tissue Specificity: Expressed in the heart, placenta, lung and pancreas.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Collagen biosynthesis and modifying enzymes (R-HSA-1650814)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopia 25, autosomal dominant	DISWXRNS	Limited	Autosomal dominant	[1]

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 Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[19]

20 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 Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[12]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[13]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[15]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[16]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[20]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Prolyl 4-hydroxylase subunit alpha-2 (P4HA2).	[23]

References

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• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
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• [8] 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.
• [9] 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.
• [10] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs. J Biomol Screen. 2007 Apr;12(3):328-40. doi: 10.1177/1087057107299261. Epub 2007 Mar 22.
• [17] Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One. 2009;4(2):e4409.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-63.
• [22] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [23] 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.