Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGZA1YR)

• DOT Name: Fumarylacetoacetase (FAH)
• Synonyms: FAA; EC 3.7.1.2; Beta-diketonase; Fumarylacetoacetate hydrolase
• Gene Name: FAH
• Related Disease:
  Methionine adenosyltransferase deficiency
  Tyrosinemia type I
  Acute liver failure
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cholestasis
  Disorder of methionine catabolism
  Fanconi's anemia
  Hepatitis B virus infection
  Inborn error of metabolism
  Liver cancer
  Liver failure
  Maleylacetoacetate isomerase deficiency
  Metabolic disorder
  Renal tubule disorder
  Seckel syndrome
  Sjogren-Larsson syndrome
  Thrombophilia
  Tyrosinemia type II
  Tyrosinemia type III
  Hepatocellular carcinoma
  Liver cirrhosis
  High blood pressure
  Colorectal carcinoma
  Fanconi anemia complementation group A
  Glioblastoma multiforme
  Melanoma
  Neoplasm
• UniProt ID: FAAA_HUMAN
• EC Number: 3.7.1.2
• Pfam ID: PF01557 ; PF09298
• Sequence:
  MSFIPVAEDSDFPIHNLPYGVFSTRGDPRPRIGVAIGDQILDLSIIKHLFTGPVLSKHQD
  VFNQPTLNSFMGLGQAAWKEARVFLQNLLSVSQARLRDDTELRKCAFISQASATMHLPAT
  IGDYTDFYSSRQHATNVGIMFRDKENALMPNWLHLPVGYHGRASSVVVSGTPIRRPMGQM
  KPDDSKPPVYGACKLLDMELEMAFFVGPGNRLGEPIPISKAHEHIFGMVLMNDWSARDIQ
  KWEYVPLGPFLGKSFGTTVSPWVVPMDALMPFAVPNPKQDPRPLPYLCHDEPYTFDINLS
  VNLKGEGMSQAATICKSNFKYMYWTMLQQLTHHSVNGCNLRPGDLLASGTISGPEPENFG
  SMLELSWKGTKPIDLGNGQTRKFLLDGDEVIITGYCQGDGYRIGFGQCAGKVLPALLPS
• Tissue Specificity: Mainly expressed in liver and kidney. Lower levels are also detected in many other tissues.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Tyrosine catabolism (R-HSA-8963684)
• BioCyc Pathway: MetaCyc:HS02536-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methionine adenosyltransferase deficiency	DIS4SI69	Definitive	Biomarker	[1]
Tyrosinemia type I	DISP4OS8	Definitive	Autosomal recessive	[2]
Acute liver failure	DIS5EZKX	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[3]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Genetic Variation	[6]
Cholestasis	DISDJJWE	Strong	Biomarker	[7]
Disorder of methionine catabolism	DISC7OZE	Strong	Biomarker	[1]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[8]
Inborn error of metabolism	DISO5FAY	Strong	Genetic Variation	[9]
Liver cancer	DISDE4BI	Strong	Genetic Variation	[6]
Liver failure	DISLGEL6	Strong	Genetic Variation	[10]
Maleylacetoacetate isomerase deficiency	DIS4JQQ8	Strong	Genetic Variation	[11]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[12]
Renal tubule disorder	DISAFXMQ	Strong	Biomarker	[13]
Seckel syndrome	DISEVUBA	Strong	Biomarker	[14]
Sjogren-Larsson syndrome	DISP943Y	Strong	Biomarker	[15]
Thrombophilia	DISQR7U7	Strong	Biomarker	[16]
Tyrosinemia type II	DIS4CW3M	Strong	Biomarker	[17]
Tyrosinemia type III	DISGH7NN	Strong	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	moderate	Genetic Variation	[18]
Liver cirrhosis	DIS4G1GX	moderate	Biomarker	[19]
High blood pressure	DISY2OHH	Disputed	Biomarker	[20]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[21]
Fanconi anemia complementation group A	DIS8PZLI	Limited	Altered Expression	[14]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[22]
Melanoma	DIS1RRCY	Limited	Biomarker	[23]
Neoplasm	DISZKGEW	Limited	Biomarker	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Fumarylacetoacetase (FAH).	[25]

21 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 Fumarylacetoacetase (FAH).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fumarylacetoacetase (FAH).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fumarylacetoacetase (FAH).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Fumarylacetoacetase (FAH).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Fumarylacetoacetase (FAH).	[30]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fumarylacetoacetase (FAH).	[31]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Fumarylacetoacetase (FAH).	[32]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Fumarylacetoacetase (FAH).	[33]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Fumarylacetoacetase (FAH).	[34]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Fumarylacetoacetase (FAH).	[35]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Fumarylacetoacetase (FAH).	[36]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Fumarylacetoacetase (FAH).	[37]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Fumarylacetoacetase (FAH).	[38]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Fumarylacetoacetase (FAH).	[39]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the splicing of Fumarylacetoacetase (FAH).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fumarylacetoacetase (FAH).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fumarylacetoacetase (FAH).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Fumarylacetoacetase (FAH).	[43]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Fumarylacetoacetase (FAH).	[44]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid affects the splicing of Fumarylacetoacetase (FAH).	[17]
5'-(N-ethyl-N-isopropyl)amiloride	DM3TPMO	Investigative	5'-(N-ethyl-N-isopropyl)amiloride affects the splicing of Fumarylacetoacetase (FAH).	[17]

References

• [1] Hypermethioninemias of genetic and non-genetic origin: A review.Am J Med Genet C Semin Med Genet. 2011 Feb 15;157C(1):3-32. doi: 10.1002/ajmg.c.30293. Epub 2011 Feb 9.
• [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] Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I.Hum Gene Ther. 1997 Mar 20;8(5):513-21. doi: 10.1089/hum.1997.8.5-513.
• [4] Dendrimer-Based Lipid Nanoparticles Deliver Therapeutic FAH mRNA to Normalize Liver Function and Extend Survival in a Mouse Model of Hepatorenal Tyrosinemia Type I.Adv Mater. 2018 Dec;30(52):e1805308. doi: 10.1002/adma.201805308. Epub 2018 Oct 25.
• [5] Mutation analysis of the Fanconi anaemia A gene in breast tumours with loss of heterozygosity at 16q24.3.Br J Cancer. 1999 Mar;79(7-8):1049-52. doi: 10.1038/sj.bjc.6690168.
• [6] Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability.Hum Mol Genet. 2001 Aug 15;10(17):1741-52. doi: 10.1093/hmg/10.17.1741.
• [7] Tyrosinaemia type I--de novo mutation in liver tissue suppressing an inborn splicing defect.J Mol Med (Berl). 2005 May;83(5):406-10. doi: 10.1007/s00109-005-0648-2. Epub 2005 Mar 10.
• [8] Studying HBV Infection and Therapy in Immune-Deficient NOD-Rag1-/-IL2RgammaC-null (NRG) Fumarylacetoacetate Hydrolase (Fah) Knockout Mice Transplanted with Human Hepatocytes.Methods Mol Biol. 2017;1540:267-276. doi: 10.1007/978-1-4939-6700-1_23.
• [9] Hereditary Tyrosinemia Type 1 in Turkey.Adv Exp Med Biol. 2017;959:157-172. doi: 10.1007/978-3-319-55780-9_15.
• [10] CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy.J Vis Exp. 2018 Mar 12;(133):56844. doi: 10.3791/56844.
• [11] Mildly elevated succinylacetone and normal liver function in compound heterozygotes with pathogenic and pseudodeficient FAH alleles.Mol Genet Metab Rep. 2017 Dec 27;14:55-58. doi: 10.1016/j.ymgmr.2017.12.002. eCollection 2018 Mar.
• [12] Hereditary tyrosinemia type I-associated mutations in fumarylacetoacetate hydrolase reduce the enzyme stability and increase its aggregation rate.J Biol Chem. 2019 Aug 30;294(35):13051-13060. doi: 10.1074/jbc.RA119.009367. Epub 2019 Jul 12.
• [13] Two missense mutations causing tyrosinemia type 1 with presence and absence of immunoreactive fumarylacetoacetase.Hum Genet. 1994 Jun;93(6):615-9. doi: 10.1007/BF00201558.
• [14] Normal expression of the Fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome.Am J Med Genet. 1999 Apr 23;83(5):388-91. doi: 10.1002/(sici)1096-8628(19990423)83:5<388::aid-ajmg9>3.0.co;2-1.
• [15] Isolation of animal cell mutants defective in long-chain fatty aldehyde dehydrogenase. Sensitivity to fatty aldehydes and Schiff's base modification of phospholipids: implications for Sj-ogren-Larsson syndrome.J Biol Chem. 1997 Sep 19;272(38):23532-9. doi: 10.1074/jbc.272.38.23532.
• [16] Dynamic changes of urinary proteins in a rat model of acute hypercoagulable state induced by tranexamic acid.J Cell Physiol. 2019 Jul;234(7):10809-10818. doi: 10.1002/jcp.27904. Epub 2018 Dec 7.
• [17] Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I. Clin Genet. 2014 Aug;86(2):167-71. doi: 10.1111/cge.12243. Epub 2013 Aug 21.
• [18] HBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism.Mol Cancer Res. 2019 Jul;17(7):1582-1593. doi: 10.1158/1541-7786.MCR-18-1127. Epub 2019 Apr 11.
• [19] Chronic Phenotype Characterization of a Large-Animal Model of Hereditary Tyrosinemia Type 1.Am J Pathol. 2017 Jan;187(1):33-41. doi: 10.1016/j.ajpath.2016.09.013. Epub 2016 Nov 14.
• [20] Identification of hypertension-related genes through an integrated genomic-transcriptomic approach.Circ Res. 2005 Apr 1;96(6):617-25. doi: 10.1161/01.RES.0000160556.52369.61. Epub 2005 Feb 24.
• [21] Reduced capacity for DNA repair synthesis in patients with or genetically predisposed to colorectal cancer.J Natl Cancer Inst. 1983 May;70(5):867-75.
• [22] Prognostic value of DNA repair genes based on stratification of glioblastomas.Oncotarget. 2017 Apr 27;8(35):58222-58230. doi: 10.18632/oncotarget.17452. eCollection 2017 Aug 29.
• [23] CDC5L drives FAH expression to promote metabolic reprogramming in melanoma.Oncotarget. 2017 Dec 7;8(69):114328-114343. doi: 10.18632/oncotarget.23107. eCollection 2017 Dec 26.
• [24] A missense mutation (Q279R) in the fumarylacetoacetate hydrolase gene, responsible for hereditary tyrosinemia, acts as a splicing mutation.BMC Genet. 2001;2:9. doi: 10.1186/1471-2156-2-9. Epub 2001 Jun 29.
• [25] 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.
• [26] 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.
• [27] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [28] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [29] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [30] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [31] 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.
• [32] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [33] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [34] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [35] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [36] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [37] 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.
• [38] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [39] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [40] Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I. Clin Genet. 2014 Aug;86(2):167-71. doi: 10.1111/cge.12243. Epub 2013 Aug 21.
• [41] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [42] 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.
• [43] 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.
• [44] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.