Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY84H6U)

• DOT Name: Prolyl 3-hydroxylase 2 (P3H2)
• Synonyms: EC 1.14.11.7; Leprecan-like protein 1; Myxoid liposarcoma-associated protein 4
• Gene Name: P3H2
• Related Disease: Myopia, high, with cataract and vitreoretinal degeneration
• UniProt ID: P3H2_HUMAN
• EC Number: 1.14.11.7
• Pfam ID: PF13640
• Sequence:
  MRERIWAPPLLLLLPLLLPPPLWGGPPDSPRRELELEPGPLQPFDLLYASGAAAYYSGDY
  ERAVRDLEAALRSHRRLREIRTRCARHCAARHPLPPPPPGEGPGAELPLFRSLLGRARCY
  RSCETQRLGGPASRHRVSEDVRSDFQRRVPYNYLQRAYIKLNQLEKAVEAAHTFFVANPE
  HMEMQQNIENYRATAGVEALQLVDREAKPHMESYNAGVKHYEADDFEMAIRHFEQALREY
  FVEDTECRTLCEGPQRFEEYEYLGYKAGLYEAIADHYMQVLVCQHECVRELATRPGRLSP
  IENFLPLHYDYLQFAYYRVGEYVKALECAKAYLLCHPDDEDVLDNVDYYESLLDDSIDPA
  SIEAREDLTMFVKRHKLESELIKSAAEGLGFSYTEPNYWIRYGGRQDENRVPSGVNVEGA
  EVHGFSMGKKLSPKIDRDLREGGPLLYENITFVYNSEQLNGTQRVLLDNVLSEEQCRELH
  SVASGIMLVGDGYRGKTSPHTPNEKFEGATVLKALKSGYEGRVPLKSARLFYDISEKARR
  IVESYFMLNSTLYFSYTHMVCRTALSGQQDRRNDLSHPIHADNCLLDPEANECWKEPPAY
  TFRDYSALLYMNDDFEGGEFIFTEMDAKTVTASIKPKCGRMISFSSGGENPHGVKAVTKG
  KRCAVALWFTLDPLYRELERIQADEVIAILDQEQQGKHELNINPKDEL
• Function: Prolyl 3-hydroxylase that catalyzes the post-translational formation of 3-hydroxyproline on collagens. Contributes to proline 3-hydroxylation of collagen COL4A1 and COL1A1 in tendons, the eye sclera and in the eye lens capsule. Has high activity with the type IV collagen COL4A1, and lower activity with COL1A1. Catalyzes hydroxylation of the first Pro in Gly-Pro-Hyp sequences where Hyp is 4-hydroxyproline. Has no activity on substrates that lack 4-hydroxyproline in the third position.
• Tissue Specificity: Expression localized to the epithelia of bile ducts and to the sacroplasm of heart muscle and skeletal muscle. In the pancreas, localized to a subpopulation of Langerhans islet cells and in the salivary gland, expressed in acinar cells (at protein level) . Expressed in adult heart, placenta, lung, liver, skeletal muscle and kidney . Detected in fetal heart, spleen, lung, liver skeletal muscle and kidney .
• 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, high, with cataract and vitreoretinal degeneration	DISV4M9R	Strong	Autosomal recessive	[1]

17 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 Prolyl 3-hydroxylase 2 (P3H2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[11]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[12]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[13]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[14]
Urethane	DM7NSI0	Phase 4	Urethane affects the expression of Prolyl 3-hydroxylase 2 (P3H2).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Prolyl 3-hydroxylase 2 (P3H2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Prolyl 3-hydroxylase 2 (P3H2).	[19]

References

• [1] Further phenotypic characterization of LEPREL1-related ectopia lentis. Ophthalmic Genet. 2019 Feb;40(1):80-82. doi: 10.1080/13816810.2018.1563618. Epub 2019 Jan 4.
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• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [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] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [14] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [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.