Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3SHY2S)

• DOT Name: Pyrroline-5-carboxylate reductase 3 (PYCR3)
• Synonyms: P5C reductase 3; P5CR 3; EC 1.5.1.2; Pyrroline-5-carboxylate reductase-like protein
• Gene Name: PYCR3
• UniProt ID: P5CR3_HUMAN
• EC Number: 1.5.1.2
• Pfam ID: PF03807 ; PF14748
• Sequence:
  MAAAEPSPRRVGFVGAGRMAGAIAQGLIRAGKVEAQHILASAPTDRNLCHFQALGCRTTH
  SNQEVLQSCLLVIFATKPHVLPAVLAEVAPVVTTEHILVSVAAGVSLSTLEELLPPNTRV
  LRVLPNLPCVVQEGAIVMARGRHVGSSETKLLQHLLEACGRCEEVPEAYVDIHTGLSGSG
  VAFVCAFSEALAEGAVKMGMPSSLAHRIAAQTLLGTAKMLLHEGQHPAQLRSDVCTPGGT
  TIYGLHALEQGGLRAATMSAVEAATCRAKELSRK
• Function: Enzyme that catalyzes the last step in proline biosynthesis. Proline is synthesized from either glutamate or ornithine; both are converted to pyrroline-5-carboxylate (P5C), and then to proline via pyrroline-5-carboxylate reductases (PYCRs). PYCRL is exclusively linked to the conversion of ornithine to proline.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway: Glutamate and glutamine metabolism (R-HSA-8964539)

Molecular Interaction Atlas (MIA) of This DOT

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 Pyrroline-5-carboxylate reductase 3 (PYCR3).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[4]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Pyrroline-5-carboxylate reductase 3 (PYCR3).	[9]

References

• [1] 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.
• [2] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [3] 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.
• [4] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [5] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [7] 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.
• [8] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.