Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT15HOJX)

• DOT Name: Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1)
• Synonyms: 10-FTHFDH; FDH; EC 1.5.1.6; Aldehyde dehydrogenase family 1 member L1
• Gene Name: ALDH1L1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Cholestasis
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Hyperthyroxinemia
  Hyperthyroxinemia, familial dysalbuminemic
  Lung cancer
  Lung carcinoma
  Neoplasm
  Neural tube defect
  Non-hodgkin lymphoma
  Obesity
  Prostate neoplasm
  Schizophrenia
  Astrocytoma
  Neurofibromatosis type 1
  Alzheimer disease
  Anxiety
  Anxiety disorder
  Lewy body dementia
  Neurodevelopmental disorder
• UniProt ID: AL1L1_HUMAN
• PDB ID: 2BW0; 2CFI; 2CQ8; 7YJJ
• EC Number: 1.5.1.6
• Pfam ID: PF00171 ; PF02911 ; PF00551 ; PF00550
• Sequence:
  MKIAVIGQSLFGQEVYCHLRKEGHEVVGVFTVPDKDGKADPLGLEAEKDGVPVFKYSRWR
  AKGQALPDVVAKYQALGAELNVLPFCSQFIPMEIISAPRHGSIIYHPSLLPRHRGASAIN
  WTLIHGDKKGGFSIFWADDGLDTGDLLLQKECEVLPDDTVSTLYNRFLFPEGIKGMVQAV
  RLIAEGKAPRLPQPEEGATYEGIQKKETAKINWDQPAEAIHNWIRGNDKVPGAWTEACEQ
  KLTFFNSTLNTSGLVPEGDALPIPGAHRPGVVTKAGLILFGNDDKMLLVKNIQLEDGKMI
  LASNFFKGAASSVLELTEAELVTAEAVRSVWQRILPKVLEVEDSTDFFKSGAASVDVVRL
  VEEVKELCDGLELENEDVYMASTFGDFIQLLVRKLRGDDEEGECSIDYVEMAVNKRTVRM
  PHQLFIGGEFVDAEGAKTSETINPTDGSVICQVSLAQVTDVDKAVAAAKDAFENGRWGKI
  SARDRGRLMYRLADLMEQHQEELATIEALDAGAVYTLALKTHVGMSIQTFRYFAGWCDKI
  QGSTIPINQARPNRNLTLTRKEPVGVCGIIIPWNYPLMMLSWKTAACLAAGNTVVIKPAQ
  VTPLTALKFAELTLKAGIPKGVVNVLPGSGSLVGQRLSDHPDVRKIGFTGSTEVGKHIMK
  SCAISNVKKVSLELGGKSPLIIFADCDLNKAVQMGMSSVFFNKGENCIAAGRLFVEDSIH
  DEFVRRVVEEVRKMKVGNPLDRDTDHGPQNHHAHLVKLMEYCQHGVKEGATLVCGGNQVP
  RPGFFFEPTVFTDVEDHMFIAKEESFGPVMIISRFADGDLDAVLSRANATEFGLASGVFT
  RDINKALYVSDKLQAGTVFVNTYNKTDVAAPFGGFKQSGFGKDLGEAALNEYLRVKTVTF
  EY
• Function: Cytosolic 10-formyltetrahydrofolate dehydrogenase that catalyzes the NADP(+)-dependent conversion of 10-formyltetrahydrofolate to tetrahydrofolate and carbon dioxide. May also have an NADP(+)-dependent aldehyde dehydrogenase activity towards formaldehyde, acetaldehyde, propionaldehyde, and benzaldehyde.
• Tissue Specificity: Highly expressed in liver, pancreas and kidney.
• KEGG Pathway:
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)
• BioCyc Pathway: MetaCyc:HS07217-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Cholestasis	DISDJJWE	Strong	Therapeutic	[3]
Hepatitis	DISXXX35	Strong	Altered Expression	[4]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Hyperthyroxinemia	DIS13CUJ	Strong	Genetic Variation	[5]
Hyperthyroxinemia, familial dysalbuminemic	DIS0BPAW	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[7]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[10]
Schizophrenia	DISSRV2N	Strong	Biomarker	[11]
Astrocytoma	DISL3V18	moderate	Altered Expression	[12]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[12]
Alzheimer disease	DISF8S70	Limited	Biomarker	[13]
Anxiety	DISIJDBA	Limited	Biomarker	[14]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[14]
Lewy body dementia	DISAE66J	Limited	Biomarker	[13]
Neurodevelopmental disorder	DIS372XH	Limited	Altered Expression	[15]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) increases the degradation of Folic acid.	[27]

2 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 Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[20]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[21]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[25]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1).	[26]

References

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• [2] Loss of ALDH1L1 folate enzyme confers a selective metabolic advantage for tumor progression.Chem Biol Interact. 2019 Apr 1;302:149-155. doi: 10.1016/j.cbi.2019.02.013. Epub 2019 Feb 20.
• [3] Exploration of Hepatoprotective Effect of Gentiopicroside on Alpha-Naphthylisothiocyanate-Induced Cholestatic Liver Injury in Rats by Comprehensive Proteomic and Metabolomic Signatures.Cell Physiol Biochem. 2018;49(4):1304-1319. doi: 10.1159/000493409. Epub 2018 Sep 17.
• [4] ALDH1L1 variant rs2276724 and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma.Oncol Rep. 2017 Sep;38(3):1451-1463. doi: 10.3892/or.2017.5822. Epub 2017 Jul 14.
• [5] Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia.Front Endocrinol (Lausanne). 2017 Nov 1;8:297. doi: 10.3389/fendo.2017.00297. eCollection 2017.
• [6] Cancer cells activate p53 in response to 10-formyltetrahydrofolate dehydrogenase expression.Biochem J. 2005 Nov 1;391(Pt 3):503-11. doi: 10.1042/BJ20050533.
• [7] Association between ALDH1L1 gene polymorphism and neural tube defects in the Chinese Han population.Neurol Sci. 2016 Jul;37(7):1049-54. doi: 10.1007/s10072-016-2527-8. Epub 2016 Mar 18.
• [8] Genetic polymorphisms in the one-carbon metabolism pathway genes and susceptibility to non-Hodgkin lymphoma.Tumour Biol. 2015 Mar;36(3):1819-34. doi: 10.1007/s13277-014-2785-0. Epub 2014 Nov 11.
• [9] Orchestrated downregulation of genes involved in oxidative metabolic pathways in obese vs. lean high-fat young male consumers.J Physiol Biochem. 2011 Mar;67(1):15-26. doi: 10.1007/s13105-010-0044-4. Epub 2010 Sep 30.
• [10] No association of single nucleotide polymorphisms in one-carbon metabolism genes with prostate cancer risk.Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3612-4. doi: 10.1158/1055-9965.EPI-08-0789.
• [11] Prefrontal cortex alterations in glia gene expression in schizophrenia with and without suicide.J Psychiatr Res. 2020 Feb;121:31-38. doi: 10.1016/j.jpsychires.2019.11.002. Epub 2019 Nov 9.
• [12] Gene expression profiling of NF-1-associated and sporadic pilocytic astrocytoma identifies aldehyde dehydrogenase 1 family member L1 (ALDH1L1) as an underexpressed candidate biomarker in aggressive subtypes.J Neuropathol Exp Neurol. 2008 Dec;67(12):1194-204. doi: 10.1097/NEN.0b013e31818fbe1e.
• [13] Glutamate Transporter GLT1 Expression in Alzheimer Disease and Dementia With Lewy Bodies.Front Aging Neurosci. 2018 Apr 26;10:122. doi: 10.3389/fnagi.2018.00122. eCollection 2018.
• [14] Longitudinal Magnetic Resonance Imaging Analysis and Histological Characterization after Spinal Cord Injury in Two Mouse Strains with Different Functional Recovery: Gliosis as a Key Factor.J Neurotrauma. 2018 Dec 15;35(24):2924-2940. doi: 10.1089/neu.2017.5613. Epub 2018 Aug 10.
• [15] Pharmacological and proteomic analyses of neonatal polyI:C-treated adult mice.Neurosci Res. 2019 Oct;147:39-47. doi: 10.1016/j.neures.2018.10.007. Epub 2018 Oct 26.
• [16] 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.
• [17] 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.
• [18] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [21] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [22] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [23] 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.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [26] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [27] Regulation of folate-mediated one-carbon metabolism by 10-formyltetrahydrofolate dehydrogenase. J Biol Chem. 2006 Jul 7;281(27):18335-42. doi: 10.1074/jbc.M510623200. Epub 2006 Apr 20.