Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDXI4H8)

• DOT Name: Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4)
• Synonyms: SDH assembly factor 4; SDHAF4
• Gene Name: SDHAF4
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: SDHF4_HUMAN
• Pfam ID: PF07896
• Sequence:
  MTPSRLPWLLSWVSATAWRAARSPLLCHSLRKTSSSQGGKSELVKQSLKKPKLPEGRFDA
  PEDSHLEKEPLEKFPDDVNPVTKEKGGPRGPEPTRYGDWERKGRCIDF
• Function: Plays an essential role in the assembly of succinate dehydrogenase (SDH), an enzyme complex (also referred to as respiratory complex II) that is a component of both the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain, and which couples the oxidation of succinate to fumarate with the reduction of ubiquinone (coenzyme Q) to ubiquinol. Binds to the flavoprotein subunit SDHA in its FAD-bound form, blocking the generation of excess reactive oxygen species (ROS) and facilitating its assembly with the iron-sulfur protein subunit SDHB into the SDH catalytic dimer.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]

11 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 dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[3]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Succinate dehydrogenase assembly factor 4, mitochondrial (SDHAF4).	[11]

References

• [1] Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia.PLoS Genet. 2011 Apr;7(4):e1001363. doi: 10.1371/journal.pgen.1001363. Epub 2011 Apr 7.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] 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.
• [8] 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.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.