Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKELL7F)

• DOT Name: Transmembrane prolyl 4-hydroxylase (P4HTM)
• Synonyms: P4H-TM; EC 1.14.11.29; Hypoxia-inducible factor prolyl hydroxylase 4; HIF-PH4; HIF-prolyl hydroxylase 4; HPH-4
• Gene Name: P4HTM
• Related Disease:
  Anxiety
  Anxiety disorder
  Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities
  Advanced cancer
  Attention deficit hyperactivity disorder
  Bone osteosarcoma
  Chronic kidney disease
  Dysautonomia
  Eye disorder
  Intellectual disability
  Neoplasm
  Osteosarcoma
  Sleep apnea syndrome
  Age-related macular degeneration
  Rhabdomyosarcoma
• UniProt ID: P4HTM_HUMAN
• PDB ID: 6TP5
• EC Number: 1.14.11.29
• Pfam ID: PF13640 ; PF13499
• Sequence:
  MAAAAVTGQRPETAAAEEASRPQWAPPDHCQAQAAAGLGDGEDAPVRPLCKPRGICSRAY
  FLVLMVFVHLYLGNVLALLLFVHYSNGDESSDPGPQHRAQGPGPEPTLGPLTRLEGIKVG
  HERKVQLVTDRDHFIRTLSLKPLLFEIPGFLTDEECRLIIHLAQMKGLQRSQILPTEEYE
  EAMSTMQVSQLDLFRLLDQNRDGHLQLREVLAQTRLGNGWWMTPESIQEMYAAIKADPDG
  DGVLSLQEFSNMDLRDFHKYMRSHKAESSELVRNSHHTWLYQGEGAHHIMRAIRQRVLRL
  TRLSPEIVELSEPLQVVRYGEGGHYHAHVDSGPVYPETICSHTKLVANESVPFETSCRYM
  TVLFYLNNVTGGGETVFPVADNRTYDEMSLIQDDVDLRDTRRHCDKGNLRVKPQQGTAVF
  WYNYLPDGQGWVGDVDDYSLHGGCLVTRGTKWIANNWINVDPSRARQALFQQEMARLARE
  GGTDSQPEWALDRAYRDARVEL
• Function: Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
• Tissue Specificity: Widely expressed with highest levels in adult pancreas, heart, skeletal muscle, brain, placenta, kidney and adrenal gland. Expressed at lower levels in epiphyseal cartilage and in fibroblasts.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety	DISIJDBA	Definitive	Altered Expression	[1]
Anxiety disorder	DISBI2BT	Definitive	Altered Expression	[1]
Hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities	DIS7252W	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[6]
Dysautonomia	DISF4MT6	Strong	Biomarker	[7]
Eye disorder	DISB52BH	Strong	Biomarker	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Sleep apnea syndrome	DISER6KS	Strong	Biomarker	[7]
Age-related macular degeneration	DIS0XS2C	moderate	Biomarker	[9]
Rhabdomyosarcoma	DISNR7MS	moderate	Posttranslational Modification	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Transmembrane prolyl 4-hydroxylase (P4HTM) decreases the response to substance of Arsenic trioxide.	[18]

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 Transmembrane prolyl 4-hydroxylase (P4HTM).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transmembrane prolyl 4-hydroxylase (P4HTM).	[17]

5 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 Transmembrane prolyl 4-hydroxylase (P4HTM).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transmembrane prolyl 4-hydroxylase (P4HTM).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane prolyl 4-hydroxylase (P4HTM).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transmembrane prolyl 4-hydroxylase (P4HTM).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transmembrane prolyl 4-hydroxylase (P4HTM).	[16]

References

• [1] Null mutation in P4h-tm leads to decreased fear and anxiety and increased social behavior in mice.Neuropharmacology. 2019 Jul 15;153:63-72. doi: 10.1016/j.neuropharm.2019.04.023. Epub 2019 Apr 25.
• [2] HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein. Clin Genet. 2022 Nov;102(5):444-450. doi: 10.1111/cge.14203. Epub 2022 Aug 19.
• [3] Apicidin upregulates PHD2 prolyl hydroxylase gene expression in cervical cancer cells.Anticancer Drugs. 2010 Jul;21(6):619-24. doi: 10.1097/cad.0b013e328339848b.
• [4] The HIDEA School-Based Screening Scale for Teachers to Detect ADHD Markers in Elementary Students.Psicothema. 2017 Aug;29(3):329-334. doi: 10.7334/psicothema2016.246.
• [5] PHD4 stimulates tumor angiogenesis in osteosarcoma cells via TGF-.Mol Cancer Res. 2013 Nov;11(11):1337-48. doi: 10.1158/1541-7786.MCR-13-0201. Epub 2013 Sep 18.
• [6] Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.Nephrol Dial Transplant. 2019 Jan 1;34(1):90-99. doi: 10.1093/ndt/gfy055.
• [7] Clinical characterization, genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome.Eur J Med Genet. 2014 Oct;57(10):543-51. doi: 10.1016/j.ejmg.2014.07.002. Epub 2014 Jul 29.
• [8] Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome). Genet Med. 2019 Oct;21(10):2355-2363. doi: 10.1038/s41436-019-0503-4. Epub 2019 Apr 3.
• [9] Lack of P4H-TM in mice results in age-related retinal and renal alterations.Hum Mol Genet. 2016 Sep 1;25(17):3810-3823. doi: 10.1093/hmg/ddw228. Epub 2016 Jul 27.
• [10] Genome-wide DNA methylation studies suggest distinct DNA methylation patterns in pediatric embryonal and alveolar rhabdomyosarcomas.Epigenetics. 2012 Apr;7(4):400-8. doi: 10.4161/epi.19463. Epub 2012 Apr 1.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] 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.
• [18] 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.