Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDWSQ0L)

• DOT Name: 2-Hydroxyacid oxidase 2 (HAO2)
• Synonyms: HAOX2; EC 1.1.3.15; (S)-2-hydroxy-acid oxidase, peroxisomal; Cell growth-inhibiting gene 16 protein; Long chain alpha-hydroxy acid oxidase; Long-chain L-2-hydroxy acid oxidase
• Gene Name: HAO2
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Familial hyperinsulinism
  Hepatocellular carcinoma
  Inborn error of metabolism
  Primary hyperoxaluria
  Primary hyperoxaluria type 1
  Cholestasis
• UniProt ID: HAOX2_HUMAN
• EC Number: 1.1.3.15
• Pfam ID: PF01070
• Sequence:
  MSLVCLTDFQAHAREQLSKSTRDFIEGGADDSITRDDNIAAFKRIRLRPRYLRDVSEVDT
  RTTIQGEEISAPICIAPTGFHCLVWPDGEMSTARAAQAAGICYITSTFASCSLEDIVIAA
  PEGLRWFQLYVHPDLQLNKQLIQRVESLGFKALVITLDTPVCGNRRHDIRNQLRRNLTLT
  DLQSPKKGNAIPYFQMTPISTSLCWNDLSWFQSITRLPIILKGILTKEDAELAVKHNVQG
  IIVSNHGGRQLDEVLASIDALTEVVAAVKGKIEVYLDGGVRTGNDVLKALALGAKCIFLG
  RPILWGLACKGEHGVKEVLNILTNEFHTSMALTGCRSVAEINRNLVQFSRL
• Function: Oxidase that catalyzes the oxidation of medium and long chain hydroxyacids such as 2-hydroxyhexadecanoate and 2-hydroxyoctanoate, to the correspondong 2-oxoacids. Its role in the oxidation of 2-hydroxy fatty acids may contribute to the general pathway of fatty acid alpha-oxidation (Probable). Active in vitro with the artificial electron acceptor 2,6-dichlorophenolindophenol (DCIP), but O2 is believed to be the physiological electron acceptor, leading to the production of H2O2. Is not active on glycolate, glyoxylate, L-lactate and 2-hydroxybutanoate.
• Tissue Specificity: Expressed in the liver and kidney.
• KEGG Pathway:
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Peroxisomal lipid metabolism (R-HSA-390918)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Familial hyperinsulinism	DISHQKQE	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[4]
Primary hyperoxaluria	DIS0L16N	Strong	Biomarker	[5]
Primary hyperoxaluria type 1	DISS210K	Strong	Biomarker	[6]
Cholestasis	DISDJJWE	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of 2-Hydroxyacid oxidase 2 (HAO2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 2-Hydroxyacid oxidase 2 (HAO2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 2-Hydroxyacid oxidase 2 (HAO2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 2-Hydroxyacid oxidase 2 (HAO2).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 2-Hydroxyacid oxidase 2 (HAO2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 2-Hydroxyacid oxidase 2 (HAO2).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 2-Hydroxyacid oxidase 2 (HAO2).	[13]

References

• [1] HAO2 inhibits malignancy of clear cell renal cell carcinoma by promoting lipid catabolic process.J Cell Physiol. 2019 Dec;234(12):23005-23016. doi: 10.1002/jcp.28861. Epub 2019 May 24.
• [2] Glycolate oxidase deficiency in a patient with congenital hyperinsulinism and unexplained hyperoxaluria.Pediatr Nephrol. 2017 Nov;32(11):2159-2163. doi: 10.1007/s00467-017-3741-1. Epub 2017 Jul 27.
• [3] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [4] Glycolate Oxidase Is a Safe and Efficient Target for Substrate Reduction Therapy in a Mouse Model of Primary Hyperoxaluria Type I.Mol Ther. 2016 Apr;24(4):719-25. doi: 10.1038/mt.2015.224. Epub 2015 Dec 22.
• [5] Specific Inhibition of Hepatic Lactate Dehydrogenase Reduces Oxalate Production in Mouse Models of Primary Hyperoxaluria.Mol Ther. 2018 Aug 1;26(8):1983-1995. doi: 10.1016/j.ymthe.2018.05.016. Epub 2018 Jun 15.
• [6] CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I.Nat Commun. 2018 Dec 21;9(1):5454. doi: 10.1038/s41467-018-07827-1.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [9] 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.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [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.