Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJB560Z)

• DOT Name: Retinal dehydrogenase 2 (ALDH1A2)
• Synonyms: RALDH 2; RalDH2; EC 1.2.1.36; Aldehyde dehydrogenase family 1 member A2; ALDH1A2; Retinaldehyde-specific dehydrogenase type 2; RALDH(II)
• Gene Name: ALDH1A2
• Related Disease: Diaphragmatic hernia 4, with cardiovascular defects
• UniProt ID: AL1A2_HUMAN
• PDB ID: 4X2Q; 6ALJ; 6B5G; 6B5H; 6B5I
• EC Number: 1.2.1.36
• Pfam ID: PF00171
• Sequence:
  MTSSKIEMPGEVKADPAALMASLHLLPSPTPNLEIKYTKIFINNEWQNSESGRVFPVYNP
  ATGEQVCEVQEADKADIDKAVQAARLAFSLGSVWRRMDASERGRLLDKLADLVERDRAVL
  ATMESLNGGKPFLQAFYVDLQGVIKTFRYYAGWADKIHGMTIPVDGDYFTFTRHEPIGVC
  GQIIPWNFPLLMFAWKIAPALCCGNTVVIKPAEQTPLSALYMGALIKEAGFPPGVINILP
  GYGPTAGAAIASHIGIDKIAFTGSTEVGKLIQEAAGRSNLKRVTLELGGKSPNIIFADAD
  LDYAVEQAHQGVFFNQGQCCTAGSRIFVEESIYEEFVRRSVERAKRRVVGSPFDPTTEQG
  PQIDKKQYNKILELIQSGVAEGAKLECGGKGLGRKGFFIEPTVFSNVTDDMRIAKEEIFG
  PVQEILRFKTMDEVIERANNSDFGLVAAVFTNDINKALTVSSAMQAGTVWINCYNALNAQ
  SPFGGFKMSGNGREMGEFGLREYSEVKTVTVKIPQKNS
• Function: Catalyzes the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively. Retinoate signaling is critical for the transcriptional control of many genes, for instance it is crucial for initiation of meiosis in both male and female (Probable). Recognizes retinal as substrate, both in its free form and when bound to cellular retinol-binding protein. Can metabolize octanal and decanal, but has only very low activity with benzaldehyde, acetaldehyde and propanal. Displays complete lack of activity with citral.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
• Reactome Pathway: RA biosynthesis pathway (R-HSA-5365859)
• BioCyc Pathway: MetaCyc:HS05232-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diaphragmatic hernia 4, with cardiovascular defects	DISKNZEZ	Strong	Autosomal recessive	[1]

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 Retinal dehydrogenase 2 (ALDH1A2).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Retinal dehydrogenase 2 (ALDH1A2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Retinal dehydrogenase 2 (ALDH1A2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[7]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[8]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Nilotinib	DM7HXWT	Approved	Nilotinib decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Abacavir	DMMN36E	Approved	Abacavir decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Polyethylene glycol	DM4I1JP	Approved	Polyethylene glycol decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Dabigatran	DMDI6R4	Approved	Dabigatran decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Metoclopramide	DMFA5MY	Approved	Metoclopramide decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
Ramelteon	DM7IW9J	Approved	Ramelteon decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[3]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[6]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram decreases the activity of Retinal dehydrogenase 2 (ALDH1A2).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[14]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Retinal dehydrogenase 2 (ALDH1A2).	[15]
Choline	DM5D9YK	Investigative	Choline affects the expression of Retinal dehydrogenase 2 (ALDH1A2).	[16]

References

• [1] Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects. Hum Mutat. 2021 May;42(5):506-519. doi: 10.1002/humu.24179. Epub 2021 Apr 1.
• [2] 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.
• [3] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] 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.
• [7] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [8] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [9] The enzymatic activity of human aldehyde dehydrogenases 1A2 and 2 (ALDH1A2 and ALDH2) is detected by Aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance. Chem Biol Interact. 2012 Jan 5;195(1):52-60.
• [10] 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.
• [11] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [16] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.