Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS2HLGD)

• DOT Name: Pyrroline-5-carboxylate reductase 2 (PYCR2)
• Synonyms: P5C reductase 2; P5CR 2; EC 1.5.1.2
• Gene Name: PYCR2
• Related Disease:
  Hypomyelinating leukodystrophy 10
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Isolated congenital microcephaly
  Leukodystrophy
  Autosomal recessive primary microcephaly
  Intellectual disability
  Melanoma
• UniProt ID: P5CR2_HUMAN
• PDB ID: 6LHM
• EC Number: 1.5.1.2
• Pfam ID: PF03807 ; PF14748
• Sequence:
  MSVGFIGAGQLAYALARGFTAAGILSAHKIIASSPEMNLPTVSALRKMGVNLTRSNKETV
  KHSDVLFLAVKPHIIPFILDEIGADVQARHIVVSCAAGVTISSVEKKLMAFQPAPKVIRC
  MTNTPVVVQEGATVYATGTHALVEDGQLLEQLMSSVGFCTEVEEDLIDAVTGLSGSGPAY
  AFMALDALADGGVKMGLPRRLAIQLGAQALLGAAKMLLDSEQHPCQLKDNVCSPGGATIH
  ALHFLESGGFRSLLINAVEASCIRTRELQSMADQEKISPAALKKTLLDRVKLESPTVSTL
  TPSSPGKLLTRSLALGGKKD
• Function: Housekeeping enzyme that catalyzes the last step in proline biosynthesis. In some cell types, such as erythrocytes, its primary function may be the generation of NADP(+). Can utilize both NAD and NADP. Has higher affinity for NADP, but higher catalytic efficiency with NADH. Involved in cellular response to oxidative stress.
• Tissue Specificity: Detected in erythrocytes (at protein level) . Expressed in fetal brain .
• 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypomyelinating leukodystrophy 10	DISZIB0Z	Definitive	Autosomal recessive	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[4]
Leukodystrophy	DISVY1TT	moderate	Genetic Variation	[4]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[4]
Intellectual disability	DISMBNXP	Limited	Biomarker	[4]
Melanoma	DIS1RRCY	Limited	Biomarker	[5]

3 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 2 (PYCR2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Pyrroline-5-carboxylate reductase 2 (PYCR2).	[15]

References

• [1] Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet. 2015 May 7;96(5):709-19. doi: 10.1016/j.ajhg.2015.03.003. Epub 2015 Apr 9.
• [2] Spatially resolved metabolomics to discover tumor-associated metabolic alterations.Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):52-57. doi: 10.1073/pnas.1808950116. Epub 2018 Dec 17.
• [3] Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma.Cell. 2019 Oct 3;179(2):561-577.e22. doi: 10.1016/j.cell.2019.08.052.
• [4] Homozygous variants in pyrroline-5-carboxylate reductase 2 (PYCR2) in patients with progressive microcephaly and hypomyelinating leukodystrophy. Am J Med Genet A. 2017 Feb;173(2):460-470. doi: 10.1002/ajmg.a.38049. Epub 2016 Nov 11.
• [5] Downregulation of pyrroline-5-carboxylate reductase-2 induces the autophagy of melanoma cells via AMPK/mTOR pathway.Tumour Biol. 2016 May;37(5):6485-91. doi: 10.1007/s13277-015-3927-8. Epub 2015 Dec 3.
• [6] 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.
• [7] 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.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.