Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRC8QCM)

• DOT Name: Prolyl 3-hydroxylase 3 (P3H3)
• Synonyms: EC 1.14.11.7; Leprecan-like protein 2; Protein B
• Gene Name: P3H3
• Related Disease:
  Adult lymphoma
  Ehlers-Danlos syndrome, kyphoscoliotic type 1
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lymphoma
  Pediatric lymphoma
  Tendinopathy
  Typhus
  Brucellosis
  Breast cancer
  Breast carcinoma
  Neoplasm
  Osteoarthritis
• UniProt ID: P3H3_HUMAN
• EC Number: 1.14.11.7
• Pfam ID: PF13640
• Sequence:
  MLRLLRPLLLLLLLPPPGSPEPPGLTQLSPGAPPQAPDLLYADGLRAYAAGAWAPAVALL
  REALRSQAALGRVRLDCGASCAADPGAALPAVLLGAPEPDSGPGPTQGSWERQLLRAALR
  RADCLTQCAARRLGPGGAARLRVGSALRDAFRRREPYNYLQRAYYQLKKLDLAAAAAHTF
  FVANPMHLQMREDMAKYRRMSGVRPQSFRDLETPPHWAAYDTGLELLGRQEAGLALPRLE
  EALQGSLAQMESCRADCEGPEEQQGAEEEEDGAASQGGLYEAIAGHWIQVLQCRQRCVGE
  TATRPGRSFPVPDFLPNQLRRLHEAHAQVGNLSQAIENVLSVLLFYPEDEAAKRALNQYQ
  AQLGEPRPGLGPREDIQRFILRSLGEKRQLYYAMEHLGTSFKDPDPWTPAALIPEALREK
  LREDQEKRPWDHEPVKPKPLTYWKDVLLLEGVTLTQDSRQLNGSERAVLDGLLTPAECGV
  LLQLAKDAAGAGARSGYRGRRSPHTPHERFEGLTVLKAAQLARAGTVGSQGAKLLLEVSE
  RVRTLTQAYFSPERPLHLSFTHLVCRSAIEGEQEQRMDLSHPVHADNCVLDPDTGECWRE
  PPAYTYRDYSGLLYLNDDFQGGDLFFTEPNALTVTARVRPRCGRLVAFSSGVENPHGVWA
  VTRGRRCALALWHTWAPEHREQEWIEAKELLQESQEEEEEEEEEMPSKDPSPEPPSRRHQ
  RVQDKTGRAPRVREEL
• Function: Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils. Required for normal hydroxylation of lysine residues in type I collagen chains in skin, bone, tendon, aorta and cornea. Required for normal skin stability via its role in hydroxylation of lysine residues in collagen alpha chains and in collagen fibril assembly. Apparently not required for normal prolyl 3-hydroxylation on collagen chains, possibly because it functions redundantly with other prolyl 3-hydroxylases.
• Tissue Specificity: Detected in fetal cartilage (at protein level) . Weak expression in heart, lung, ovary and skeletal muscle .
• Reactome Pathway: Collagen biosynthesis and modifying enzymes (R-HSA-1650814)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[1]
Ehlers-Danlos syndrome, kyphoscoliotic type 1	DISVE04H	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[1]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[1]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[1]
Lymphoma	DISN6V4S	Strong	Altered Expression	[1]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[1]
Tendinopathy	DISJH7UX	Strong	Biomarker	[3]
Typhus	DISJ5JX1	Strong	Genetic Variation	[4]
Brucellosis	DISEAYGH	Disputed	Biomarker	[5]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[1]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]
Osteoarthritis	DIS05URM	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Prolyl 3-hydroxylase 3 (P3H3) affects the response to substance of Temozolomide.	[14]
DTI-015	DMXZRW0	Approved	Prolyl 3-hydroxylase 3 (P3H3) affects the response to substance of DTI-015.	[14]

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 3-hydroxylase 3 (P3H3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Prolyl 3-hydroxylase 3 (P3H3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Prolyl 3-hydroxylase 3 (P3H3).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Prolyl 3-hydroxylase 3 (P3H3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolyl 3-hydroxylase 3 (P3H3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Prolyl 3-hydroxylase 3 (P3H3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prolyl 3-hydroxylase 3 (P3H3).	[13]

References

• [1] Collagen prolyl hydroxylase 3 has a tumor suppressive activity in human lung cancer.Exp Cell Res. 2018 Feb 1;363(1):121-128. doi: 10.1016/j.yexcr.2017.12.020. Epub 2017 Dec 23.
• [2] P3h3-null and Sc65-null Mice Phenocopy the Collagen Lysine Under-hydroxylation and Cross-linking Abnormality of Ehlers-Danlos Syndrome Type VIA.J Biol Chem. 2017 Mar 3;292(9):3877-3887. doi: 10.1074/jbc.M116.762245. Epub 2017 Jan 23.
• [3] Genome-wide analysis identifies differential promoter methylation of Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12 in murine tendinopathy.J Orthop Res. 2017 May;35(5):947-955. doi: 10.1002/jor.23393. Epub 2016 Aug 29.
• [4] Phylogenetic analysis of the rompB genes of Rickettsia felis and Rickettsia prowazekii European-human and North American flying-squirrel strains.Am J Trop Med Hyg. 2000 May;62(5):598-603. doi: 10.4269/ajtmh.2000.62.598.
• [5] The identification of two protective DNA vaccines from a panel of five plasmid constructs encoding Brucella melitensis 16M genes.Vaccine. 2007 Jan 2;25(1):43-54. doi: 10.1016/j.vaccine.2006.07.046. Epub 2006 Aug 4.
• [6] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.