Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCH86VF)

• DOT Name: Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2)
• Synonyms: Mitochondrial 10-FTHFDH; mtFDH; EC 1.5.1.6; Aldehyde dehydrogenase family 1 member L2
• Gene Name: ALDH1L2
• Related Disease: Advanced cancer
• UniProt ID: AL1L2_HUMAN
• EC Number: 1.5.1.6
• Pfam ID: PF00171 ; PF02911 ; PF00551 ; PF00550
• Sequence:
  MLRRGSQALRRFSTGRVYFKNKLKLALIGQSLFGQEVYSHLRKEGHRVVGVFTVPDKDGK
  ADPLALAAEKDGTPVFKLPKWRVKGKTIKEVAEAYRSVGAELNVLPFCTQFIPMDIIDSP
  KHGSIIYHPSILPRHRGASAINWTLIMGDKKAGFSVFWADDGLDTGPILLQRSCDVEPND
  TVDALYNRFLFPEGIKAMVEAVQLIADGKAPRIPQPEEGATYEGIQKKENAEISWDQSAE
  VLHNWIRGHDKVPGAWTEINGQMVTFYGSTLLNSSVPPGEPLEIKGAKKPGLVTKNGLVL
  FGNDGKALTVRNLQFEDGKMIPASQYFSTGETSVVELTAEEVKVAETIKVIWAGILSNVP
  IIEDSTDFFKSGASSMDVARLVEEIRQKCGGLQLQNEDVYMATKFEGFIQKVVRKLRGED
  QEVELVVDYISKEVNEIMVKMPYQCFINGQFTDADDGKTYDTINPTDGSTICKVSYASLA
  DVDKAVAAAKDAFENGEWGRMNARERGRLMYRLADLLEENQEELATIEALDSGAVYTLAL
  KTHIGMSVQTFRYFAGWCDKIQGSTIPINQARPNRNLTFTKKEPLGVCAIIIPWNYPLMM
  LAWKSAACLAAGNTLVLKPAQVTPLTALKFAELSVKAGFPKGVINIIPGSGGIAGQRLSE
  HPDIRKLGFTGSTPIGKQIMKSCAVSNLKKVSLELGGKSPLIIFNDCELDKAVRMGMGAV
  FFNKGENCIAAGRLFVEESIHDEFVTRVVEEIKKMKIGDPLDRSTDHGPQNHKAHLEKLL
  QYCETGVKEGATLVYGGRQVQRPGFFMEPTVFTDVEDYMYLAKEESFGPIMVISKFQNGD
  IDGVLQRANSTEYGLASGVFTRDINKAMYVSEKLEAGTVFINTYNKTDVAAPFGGVKQSG
  FGKDLGEEALNEYLKTKTVTLEY
• Function: Mitochondrial 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide.
• Tissue Specificity: Highly expressed in pancreas, heart, brain and skeletal muscle.
• KEGG Pathway:
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)
• BioCyc Pathway: MetaCyc:HS06100-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
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Tetrahydrofolic acid	DMH15UV	Approved	Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2) increases the chemical synthesis of Tetrahydrofolic acid.	[19]

16 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 Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[8]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[9]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[10]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[11]
Mitotane	DMU1GX0	Approved	Mitotane increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[18]

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 Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mitochondrial 10-formyltetrahydrofolate dehydrogenase (ALDH1L2).	[13]

References

• [1] ALDH1L1 and ALDH1L2 Folate Regulatory Enzymes in Cancer.Adv Exp Med Biol. 2018;1032:127-143. doi: 10.1007/978-3-319-98788-0_10.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] 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.
• [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] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [9] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [10] Anti-inflammatory agent indomethacin reduces invasion and alters metabolism in a human breast cancer cell line. Neoplasia. 2007 Mar;9(3):222-35.
• [11] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [12] Effects of mitotane on gene expression in the adrenocortical cell line NCI-H295R: a microarray study. Pharmacogenomics. 2012 Sep;13(12):1351-61. doi: 10.2217/pgs.12.116.
• [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.
• [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] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [16] 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.
• [17] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [18] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [19] Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase. Chem Biol Interact. 2011 May 30;191(1-3):129-36. doi: 10.1016/j.cbi.2011.01.008. Epub 2011 Jan 14.