Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2TFW25)

• DOT Name: Prolyl 3-hydroxylase 1 (P3H1)
• Synonyms: EC 1.14.11.7; Growth suppressor 1; Leucine- and proline-enriched proteoglycan 1; Leprecan-1
• Gene Name: P3H1
• Related Disease:
  Osteogenesis imperfecta type 8
  Osteogenesis imperfecta type 2
  Osteogenesis imperfecta type 3
• UniProt ID: P3H1_HUMAN
• EC Number: 1.14.11.7
• Pfam ID: PF13640
• Sequence:
  MAVRALKLLTTLLAVVAAASQAEVESEAGWGMVTPDLLFAEGTAAYARGDWPGVVLSMER
  ALRSRAALRALRLRCRTQCAADFPWELDPDWSPSPAQASGAAALRDLSFFGGLLRRAACL
  RRCLGPPAAHSLSEEMELEFRKRSPYNYLQVAYFKINKLEKAVAAAHTFFVGNPEHMEMQ
  QNLDYYQTMSGVKEADFKDLETQPHMQEFRLGVRLYSEEQPQEAVPHLEAALQEYFVAYE
  ECRALCEGPYDYDGYNYLEYNADLFQAITDHYIQVLNCKQNCVTELASHPSREKPFEDFL
  PSHYNYLQFAYYNIGNYTQAVECAKTYLLFFPNDEVMNQNLAYYAAMLGEEHTRSIGPRE
  SAKEYRQRSLLEKELLFFAYDVFGIPFVDPDSWTPEEVIPKRLQEKQKSERETAVRISQE
  IGNLMKEIETLVEEKTKESLDVSRLTREGGPLLYEGISLTMNSKLLNGSQRVVMDGVISD
  HECQELQRLTNVAATSGDGYRGQTSPHTPNEKFYGVTVFKALKLGQEGKVPLQSAHLYYN
  VTEKVRRIMESYFRLDTPLYFSYSHLVCRTAIEEVQAERKDDSHPVHVDNCILNAETLVC
  VKEPPAYTFRDYSAILYLNGDFDGGNFYFTELDAKTVTAEVQPQCGRAVGFSSGTENPHG
  VKAVTRGQRCAIALWFTLDPRHSERDRVQADDLVKMLFSPEEMDLSQEQPLDAQQGPPEP
  AQESLSGSESKPKDEL
• Function: Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). Has prolyl 3-hydroxylase activity catalyzing the post-translational formation of 3-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens, especially types IV and V. May be involved in the secretory pathway of cells. Has growth suppressive activity in fibroblasts.
• Reactome Pathway: Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
• BioCyc Pathway: MetaCyc:HS04122-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteogenesis imperfecta type 8	DISGVEAN	Definitive	Autosomal recessive	[1]
Osteogenesis imperfecta type 2	DISMGSS3	Supportive	Autosomal dominant	[2]
Osteogenesis imperfecta type 3	DISFJVSJ	Supportive	Autosomal dominant	[2]

1 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 1 (P3H1).	[3]

6 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 3-hydroxylase 1 (P3H1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolyl 3-hydroxylase 1 (P3H1).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Prolyl 3-hydroxylase 1 (P3H1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Prolyl 3-hydroxylase 1 (P3H1).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Prolyl 3-hydroxylase 1 (P3H1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Prolyl 3-hydroxylase 1 (P3H1).	[9]

References

• [1] Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J Med Genet. 2009 Apr;46(4):233-41. doi: 10.1136/jmg.2008.062729. Epub 2008 Dec 16.
• [2] Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011 May;155A(5):943-68. doi: 10.1002/ajmg.a.33909. Epub 2011 Mar 15.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] 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.