Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW7D1SV)

• DOT Name: 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL)
• Synonyms: HPD-like protein; EC 1.13.-.-; Glyoxalase domain-containing protein 1
• Gene Name: HPDL
• Related Disease:
  Hepatocellular carcinoma
  Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities
  Leigh syndrome
• UniProt ID: HPDL_HUMAN
• EC Number: 1.13.-.-
• Sequence:
  MAAPALRLCHIAFHVPAGQPLARNLQRLFGFQPLASREVDGWRQLALRSGDAVFLVNEGA
  GSGEPLYGLDPRHAVPSATNLCFDVADAGAATRELAALGCSVPVPPVRVRDAQGAATYAV
  VSSPAGILSLTLLERAGYRGPFLPGFRPVSSAPGPGWVSRVDHLTLACTPGSSPTLLRWF
  HDCLGFCHLPLSPGEDPELGLEMTAGFGLGGLRLTALQAQPGSIVPTLVLAESLPGATTR
  QDQVEQFLARHKGPGLQHVGLYTPNIVEATEGVATAGGQFLAPPGAYYQQPGKERQIRAA
  GHEPHLLARQGILLDGDKGKFLLQVFTKSLFTEDTFFLELIQRQGATGFGQGNIRALWQS
  VQEQSARSQEA
• Function: May have dioxygenase activity.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[1]
Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities	DIS4YFC4	Strong	Autosomal recessive	[2]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[7]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[8]

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 increases the methylation of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL).	[9]

References

• [1] Methylation of IRAK3 is a novel prognostic marker in hepatocellular carcinoma.World J Gastroenterol. 2015 Apr 7;21(13):3960-9. doi: 10.3748/wjg.v21.i13.3960.
• [2] Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia. Am J Hum Genet. 2020 Aug 6;107(2):364-373. doi: 10.1016/j.ajhg.2020.06.015. Epub 2020 Jul 23.
• [3] 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.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] 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.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] 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.
• [10] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [11] 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.
• [12] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.