Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV04QE5)

• DOT Name: Prolyl 4-hydroxylase subunit alpha-1 (P4HA1)
• Synonyms: 4-PH alpha-1; EC 1.14.11.2; Procollagen-proline,2-oxoglutarate-4-dioxygenase subunit alpha-1
• Gene Name: P4HA1
• UniProt ID: P4HA1_HUMAN
• PDB ID: 1TJC; 2V5F; 2YQ8; 4BT8; 4BT9; 4BTA; 4BTB
• EC Number: 1.14.11.2
• Pfam ID: PF13640 ; PF08336
• Sequence:
  MIWYILIIGILLPQSLAHPGFFTSIGQMTDLIHTEKDLVTSLKDYIKAEEDKLEQIKKWA
  EKLDRLTSTATKDPEGFVGHPVNAFKLMKRLNTEWSELENLVLKDMSDGFISNLTIQRQY
  FPNDEDQVGAAKALLRLQDTYNLDTDTISKGNLPGVKHKSFLTAEDCFELGKVAYTEADY
  YHTELWMEQALRQLDEGEISTIDKVSVLDYLSYAVYQQGDLDKALLLTKKLLELDPEHQR
  ANGNLKYFEYIMAKEKDVNKSASDDQSDQKTTPKKKGVAVDYLPERQKYEMLCRGEGIKM
  TPRRQKKLFCRYHDGNRNPKFILAPAKQEDEWDKPRIIRFHDIISDAEIEIVKDLAKPRL
  RRATISNPITGDLETVHYRISKSAWLSGYENPVVSRINMRIQDLTGLDVSTAEELQVANY
  GVGGQYEPHFDFARKDEPDAFKELGTGNRIATWLFYMSDVSAGGATVFPEVGASVWPKKG
  TAVFWYNLFASGEGDYSTRHAACPVLVGNKWVSNKWLHERGQEFRRPCTLSELE
• 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, liver, skeletal muscle, kidney, placenta, lung and pancreas.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
• BioCyc Pathway: MetaCyc:HS04613-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Prolyl 4-hydroxylase subunit alpha-1 (P4HA1) affects the response to substance of Mitoxantrone.	[22]

2 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 Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[1]
Marinol	DM70IK5	Approved	Marinol increases the methylation of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[12]

26 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 Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[13]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[7]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[7]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[7]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[18]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[19]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[20]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Prolyl 4-hydroxylase subunit alpha-1 (P4HA1).	[21]

References

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• [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] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
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• [12] Epigenetic activation of O-linked -N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia. EBioMedicine. 2020 Apr;54:102678. doi: 10.1016/j.ebiom.2020.102678. Epub 2020 Apr 6.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [15] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [16] 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.
• [17] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.
• [20] Proteomic analysis of proteins associated with cellular senescence by calorie restriction in mesenchymal stem cells. In Vitro Cell Dev Biol Anim. 2012 Mar;48(3):186-95.
• [21] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.