Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQY6ZSF)

• DOT Name: 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1)
• Synonyms: ALAS-H; EC 2.3.1.37; 5-aminolevulinic acid synthase 1; Delta-ALA synthase 1; Delta-aminolevulinate synthase 1
• Gene Name: ALAS1
• UniProt ID: HEM1_HUMAN
• EC Number: 2.3.1.37
• Pfam ID: PF00155 ; PF09029
• Sequence:
  MESVVRRCPFLSRVPQAFLQKAGKSLLFYAQNCPKMMEVGAKPAPRALSTAAVHYQQIKE
  TPPASEKDKTAKAKVQQTPDGSQQSPDGTQLPSGHPLPATSQGTASKCPFLAAQMNQRGS
  SVFCKASLELQEDVQEMNAVRKEVAETSAGPSVVSVKTDGGDPSGLLKNFQDIMQKQRPE
  RVSHLLQDNLPKSVSTFQYDRFFEKKIDEKKNDHTYRVFKTVNRRAHIFPMADDYSDSLI
  TKKQVSVWCSNDYLGMSRHPRVCGAVMDTLKQHGAGAGGTRNISGTSKFHVDLERELADL
  HGKDAALLFSSCFVANDSTLFTLAKMMPGCEIYSDSGNHASMIQGIRNSRVPKYIFRHND
  VSHLRELLQRSDPSVPKIVAFETVHSMDGAVCPLEELCDVAHEFGAITFVDEVHAVGLYG
  ARGGGIGDRDGVMPKMDIISGTLGKAFGCVGGYIASTSSLIDTVRSYAAGFIFTTSLPPM
  LLAGALESVRILKSAEGRVLRRQHQRNVKLMRQMLMDAGLPVVHCPSHIIPVRVADAAKN
  TEVCDELMSRHNIYVQAINYPTVPRGEELLRIAPTPHHTPQMMNYFLENLLVTWKQVGLE
  LKPHSSAECNFCRRPLHFEVMSEREKSYFSGLSKLVSAQA
• Function: Catalyzes the pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products.
• KEGG Pathway:
  Glycine, serine and threonine metabolism (hsa00260)
  Porphyrin metabolism (hsa00860)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway:
  PPARA activates gene expression (R-HSA-1989781)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Heme biosynthesis (R-HSA-189451)
• BioCyc Pathway: MetaCyc:HS00424-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[14]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[15]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[3]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[21]
Hyperforin	DM2L3PE	Investigative	Hyperforin increases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[15]
Heme	DMGC287	Investigative	Heme decreases the expression of 5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1).	[22]

References

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• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] 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.
• [8] 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.
• [9] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [10] 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.
• [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] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [13] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [14] 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.
• [15] No activation of human pregnane X receptor by hyperforin-related phloroglucinols. J Pharmacol Exp Ther. 2014 Mar;348(3):393-400.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [19] 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.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [22] Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. J Biol Chem. 2011 Jul 29;286(30):26424-30. doi: 10.1074/jbc.M110.215772. Epub 2011 Jun 9.