Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLV63QV)

• DOT Name: Glyoxylate reductase/hydroxypyruvate reductase (GRHPR)
• Synonyms: EC 1.1.1.79; EC 1.1.1.81
• Gene Name: GRHPR
• Related Disease:
  Chronic renal failure
  End-stage renal disease
  Primary hyperoxaluria type 2
  Atypical hemolytic uremic syndrome
  Hemolytic-uremic syndrome
  Nephrocalcinosis
  Primary hyperoxaluria
  Primary hyperoxaluria type 1
  Prostate cancer
  Prostate neoplasm
• UniProt ID: GRHPR_HUMAN
• PDB ID: 2GCG; 2H1S; 2Q50; 2WWR
• EC Number: 1.1.1.79; 1.1.1.81
• Pfam ID: PF00389 ; PF02826
• Sequence:
  MRPVRLMKVFVTRRIPAEGRVALARAADCEVEQWDSDEPIPAKELERGVAGAHGLLCLLS
  DHVDKRILDAAGANLKVISTMSVGIDHLALDEIKKRGIRVGYTPDVLTDTTAELAVSLLL
  TTCRRLPEAIEEVKNGGWTSWKPLWLCGYGLTQSTVGIIGLGRIGQAIARRLKPFGVQRF
  LYTGRQPRPEEAAEFQAEFVSTPELAAQSDFIVVACSLTPATEGLCNKDFFQKMKETAVF
  INISRGDVVNQDDLYQALASGKIAAAGLDVTSPEPLPTNHPLLTLKNCVILPHIGSATHR
  TRNTMSLLAANNLLAGLRGEPMPSELKL
• Function: Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate, oxidizes D-glycerate to hydroxypyruvate.
• Tissue Specificity: Ubiquitous. Most abundantly expressed in the liver.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Pyruvate metabolism (hsa00620)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:HS06275-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
End-stage renal disease	DISXA7GG	Definitive	Genetic Variation	[1]
Primary hyperoxaluria type 2	DISGZT3W	Definitive	Autosomal recessive	[2]
Atypical hemolytic uremic syndrome	DIS6FUDJ	Strong	Altered Expression	[3]
Hemolytic-uremic syndrome	DISSCBGW	Strong	Biomarker	[3]
Nephrocalcinosis	DIS5ZVJP	Strong	Genetic Variation	[4]
Primary hyperoxaluria	DIS0L16N	Strong	Genetic Variation	[1]
Primary hyperoxaluria type 1	DISS210K	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]

8 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 Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Glyoxylate reductase/hydroxypyruvate reductase (GRHPR).	[14]

References

• [1] Targeting kidney inflammation as a new therapy for primary hyperoxaluria?.Nephrol Dial Transplant. 2019 Jun 1;34(6):908-914. doi: 10.1093/ndt/gfy239.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Hemolytic Uremic Syndrome in an Infant with Primary Hyperoxaluria Type II: An Unreported Clinical Association.Nephron. 2019;142(3):264-270. doi: 10.1159/000497823. Epub 2019 Mar 19.
• [4] Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis andnephrocalcinosis.Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025. Epub 2017 Oct 12.
• [5] An update on primary hyperoxaluria.Nat Rev Nephrol. 2012 Jun 12;8(8):467-75. doi: 10.1038/nrneph.2012.113.
• [6] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [7] 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.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [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] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.