Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDWEI6C)

• DOT Name: Ferrochelatase, mitochondrial (FECH)
• Synonyms: EC 4.98.1.1; Heme synthase; Protoheme ferro-lyase
• Gene Name: FECH
• Related Disease:
  Protoporphyria, erythropoietic, 1
  Autosomal erythropoietic protoporphyria
• UniProt ID: HEMH_HUMAN
• PDB ID: 1HRK; 2HRC; 2HRE; 2PNJ; 2PO5; 2PO7; 2QD1; 2QD2; 2QD3; 2QD4; 2QD5; 3AQI; 3HCN; 3HCO; 3HCP; 3HCR; 3W1W; 4F4D; 4KLA; 4KLC; 4KLR; 4KMM; 4MK4; 7CT7; 7CTC
• EC Number: 4.98.1.1
• Pfam ID: PF00762
• Sequence:
  MRSLGANMAAALRAAGVLLRDPLASSSWRVCQPWRWKSGAAAAAVTTETAQHAQGAKPQV
  QPQKRKPKTGILMLNMGGPETLGDVHDFLLRLFLDRDLMTLPIQNKLAPFIAKRRTPKIQ
  EQYRRIGGGSPIKIWTSKQGEGMVKLLDELSPNTAPHKYYIGFRYVHPLTEEAIEEMERD
  GLERAIAFTQYPQYSCSTTGSSLNAIYRYYNQVGRKPTMKWSTIDRWPTHHLLIQCFADH
  ILKELDHFPLEKRSEVVILFSAHSLPMSVVNRGDPYPQEVSATVQKVMERLEYCNPYRLV
  WQSKVGPMPWLGPQTDESIKGLCERGRKNILLVPIAFTSDHIETLYELDIEYSQVLAKEC
  GVENIRRAESLNGNPLFSKALADLVHSHIQSNELCSKQLTLSCPLCVNPVCRETKSFFTS
  QQL
• Function: Catalyzes the ferrous insertion into protoporphyrin IX.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS00891-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Protoporphyria, erythropoietic, 1	DIS6PGXC	Definitive	Autosomal recessive	[1]
Autosomal erythropoietic protoporphyria	DISFG29C	Supportive	Autosomal dominant	[2]

31 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 Ferrochelatase, mitochondrial (FECH).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ferrochelatase, mitochondrial (FECH).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ferrochelatase, mitochondrial (FECH).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ferrochelatase, mitochondrial (FECH).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ferrochelatase, mitochondrial (FECH).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ferrochelatase, mitochondrial (FECH).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Ferrochelatase, mitochondrial (FECH).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Ferrochelatase, mitochondrial (FECH).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Ferrochelatase, mitochondrial (FECH).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Ferrochelatase, mitochondrial (FECH).	[7]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Ferrochelatase, mitochondrial (FECH).	[7]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Ferrochelatase, mitochondrial (FECH).	[7]
Isoniazid	DM5JVS3	Approved	Isoniazid decreases the expression of Ferrochelatase, mitochondrial (FECH).	[13]
Benzoic acid	DMKB9FI	Approved	Benzoic acid increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ferrochelatase, mitochondrial (FECH).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ferrochelatase, mitochondrial (FECH).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Ferrochelatase, mitochondrial (FECH).	[11]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ferrochelatase, mitochondrial (FECH).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ferrochelatase, mitochondrial (FECH).	[17]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ferrochelatase, mitochondrial (FECH).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Ferrochelatase, mitochondrial (FECH).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Ferrochelatase, mitochondrial (FECH).	[20]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Ferrochelatase, mitochondrial (FECH).	[9]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the activity of Ferrochelatase, mitochondrial (FECH).	[21]
methyl salicylate	DMKCG8H	Investigative	methyl salicylate increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]
2-Propanol, Isopropanol	DML5O0H	Investigative	2-Propanol, Isopropanol increases the expression of Ferrochelatase, mitochondrial (FECH).	[12]

References

• [1] 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.
• [2] Erythropoietic Protoporphyria, Autosomal Recessive. 2012 Sep 27 [updated 2017 Sep 7]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] 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.
• [9] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
• [13] The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci. 2019 Mar 1;168(1):209-224. doi: 10.1093/toxsci/kfy294.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [20] Microphysiological system modeling of ochratoxin A-associated nephrotoxicity. Toxicology. 2020 Nov;444:152582. doi: 10.1016/j.tox.2020.152582. Epub 2020 Sep 6.
• [21] Metal inhibition of ferrochelatase activity in human lymphocytes. Clin Chim Acta. 1990 Apr 13;188(1):1-13. doi: 10.1016/0009-8981(90)90141-e.