Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF3TBTK)

• DOT Name: Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1)
• Synonyms: EC 1.2.1.24; Aldehyde dehydrogenase family 5 member A1; NAD(+)-dependent succinic semialdehyde dehydrogenase
• Gene Name: ALDH5A1
• Related Disease: Succinic semialdehyde dehydrogenase deficiency
• UniProt ID: SSDH_HUMAN
• PDB ID: 2W8N; 2W8O; 2W8P; 2W8Q; 2W8R
• EC Number: 1.2.1.24
• Pfam ID: PF00171
• Sequence:
  MATCIWLRSCGARRLGSTFPGCRLRPRAGGLVPASGPAPGPAQLRCYAGRLAGLSAALLR
  TDSFVGGRWLPAAATFPVQDPASGAALGMVADCGVREARAAVRAAYEAFCRWREVSAKER
  SSLLRKWYNLMIQNKDDLARIITAESGKPLKEAHGEILYSAFFLEWFSEEARRVYGDIIH
  TPAKDRRALVLKQPIGVAAVITPWNFPSAMITRKVGAALAAGCTVVVKPAEDTPFSALAL
  AELASQAGIPSGVYNVIPCSRKNAKEVGEAICTDPLVSKISFTGSTTTGKILLHHAANSV
  KRVSMELGGLAPFIVFDSANVDQAVAGAMASKFRNTGQTCVCSNQFLVQRGIHDAFVKAF
  AEAMKKNLRVGNGFEEGTTQGPLINEKAVEKVEKQVNDAVSKGATVVTGGKRHQLGKNFF
  EPTLLCNVTQDMLCTHEETFGPLAPVIKFDTEEEAIAIANAADVGLAGYFYSQDPAQIWR
  VAEQLEVGMVGVNEGLISSVECPFGGVKQSGLGREGSKYGIDEYLELKYVCYGGL
• Function: Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
• Tissue Specificity: Brain, pancreas, heart, liver, skeletal muscle and kidney. Lower in placenta.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Butanoate metabolism (hsa00650)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Degradation of GABA (R-HSA-916853)
• BioCyc Pathway: MetaCyc:HS03550-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
Succinic semialdehyde dehydrogenase deficiency	DISVYC3M	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Gamma hydroxybutyric acid	DMGBKVD	Approved	Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1) increases the abundance of Gamma hydroxybutyric acid.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[11]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[12]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Succinate-semialdehyde dehydrogenase, mitochondrial (ALDH5A1).	[18]

References

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• [2] 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.
• [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] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Vigabatrin improves paroxysmal dystonia in succinic semialdehyde dehydrogenase deficiency. Neurology. 2007 Apr 17;68(16):1320-1. doi: 10.1212/01.wnl.0000259537.54082.6d.