Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7XETW4)

• DOT Name: 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1)
• Synonyms: EC 4.1.3.16; Dihydrodipicolinate synthase-like; DHDPS-like protein; Probable 2-keto-4-hydroxyglutarate aldolase; Probable KHG-aldolase; Protein 569272
• Gene Name: HOGA1
• Related Disease:
  Chronic renal failure
  End-stage renal disease
  Primary hyperoxaluria type 3
  Nephrolithiasis, calcium oxalate
  Primary hyperoxaluria
  Cholestasis
• UniProt ID: HOGA1_HUMAN
• PDB ID: 3S5N; 3S5O
• EC Number: 4.1.3.16
• Pfam ID: PF00701
• Sequence:
  MLGPQVWSSVRQGLSRSLSRNVGVWASGEGKKVDIAGIYPPVTTPFTATAEVDYGKLEEN
  LHKLGTFPFRGFVVQGSNGEFPFLTSSERLEVVSRVRQAMPKNRLLLAGSGCESTQATVE
  MTVSMAQVGADAAMVVTPCYYRGRMSSAALIHHYTKVADLSPIPVVLYSVPANTGLDLPV
  DAVVTLSQHPNIVGMKDSGGDVTRIGLIVHKTRKQDFQVLAGSAGFLMASYALGAVGGVC
  ALANVLGAQVCQLERLCCTGQWEDAQKLQHRLIEPNAAVTRRFGIPGLKKIMDWFGYYGG
  PCRAPLQELSPAEEEALRMDFTSNGWL
• Function: Catalyzes the final step in the metabolic pathway of hydroxyproline.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Glyoxylate and dicarboxylate metabolism (hsa00630)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:G66-31234-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 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 3	DISUMMRM	Definitive	Autosomal recessive	[2]
Nephrolithiasis, calcium oxalate	DIS5J79C	Strong	Altered Expression	[3]
Primary hyperoxaluria	DIS0L16N	Strong	Genetic Variation	[1]
Cholestasis	DISDJJWE	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[9]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (HOGA1).	[12]

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] Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis.Clin J Am Soc Nephrol. 2011 Sep;6(9):2289-95. doi: 10.2215/CJN.02760311.
• [4] 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.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [9] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.