Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHM9GSH)

• DOT Name: Delta-aminolevulinic acid dehydratase (ALAD)
• Synonyms: ALADH; EC 4.2.1.24; Porphobilinogen synthase
• Gene Name: ALAD
• Related Disease: Porphyria due to ALA dehydratase deficiency
• UniProt ID: HEM2_HUMAN
• PDB ID: 1E51; 1PV8; 5HMS; 5HNR
• EC Number: 4.2.1.24
• Pfam ID: PF00490
• Sequence:
  MQPQSVLHSGYFHPLLRAWQTATTTLNASNLIYPIFVTDVPDDIQPITSLPGVARYGVKR
  LEEMLRPLVEEGLRCVLIFGVPSRVPKDERGSAADSEESPAIEAIHLLRKTFPNLLVACD
  VCLCPYTSHGHCGLLSENGAFRAEESRQRLAEVALAYAKAGCQVVAPSDMMDGRVEAIKE
  ALMAHGLGNRVSVMSYSAKFASCFYGPFRDAAKSSPAFGDRRCYQLPPGARGLALRAVDR
  DVREGADMLMVKPGMPYLDIVREVKDKHPDLPLAVYHVSGEFAMLWHGAQAGAFDLKAAV
  LEAMTAFRRAGADIIITYYTPQLLQWLKEE
• Function: Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen.
• KEGG Pathway:
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS07501-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
Porphyria due to ALA dehydratase deficiency	DIS3EXTY	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Delta-aminolevulinic acid dehydratase (ALAD) increases the Porphyria ADR of Carbamazepine.	[19]
Topotecan	DMP6G8T	Approved	Delta-aminolevulinic acid dehydratase (ALAD) affects the response to substance of Topotecan.	[20]

24 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 Delta-aminolevulinic acid dehydratase (ALAD).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[7]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[7]
Nicotine	DMWX5CO	Approved	Nicotine decreases the activity of Delta-aminolevulinic acid dehydratase (ALAD).	[9]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[10]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[11]
Melphalan	DMOLNHF	Approved	Melphalan decreases the activity of Delta-aminolevulinic acid dehydratase (ALAD).	[12]
Estrone	DM5T6US	Approved	Estrone decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[7]
Mestranol	DMG3F94	Approved	Mestranol decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[14]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[16]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Delta-aminolevulinic acid dehydratase (ALAD).	[17]
1,4-Dithiothreitol	DMIFOXE	Investigative	1,4-Dithiothreitol increases the activity of Delta-aminolevulinic acid dehydratase (ALAD).	[18]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] Comparative inhibition of enzymes of human erythrocytes and plasma in vitro by agricultural chemicals. Arch Environ Contam Toxicol. 1996 Jul;31(1):107-14.
• [10] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [11] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [12] delta-Aminolevulinate dehydratase activity and oxidative stress during melphalan and cyclophosphamide-BCNU-etoposide (CBV) conditioning regimens in autologous bone marrow transplantation patients. Pharmacol Res. 2009 Apr;59(4):279-84.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [16] 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.
• [17] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [18] A comparison of the effects of inorganic and alkyllead compounds on human erythrocytic delta-aminolevulinic acid dehydratase (ALAD) activity in vitro. J Appl Toxicol. 1991 Apr;11(2):103-10.
• [19] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.