Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDG5VW7)

• DOT Name: Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1)
• Synonyms: SDH assembly factor 1; SDHAF1; LYR motif-containing protein 8
• Gene Name: SDHAF1
• Related Disease:
  Cardiomyopathy
  Mitochondrial complex II deficiency, nuclear type 1
  Mitochondrial disease
  Obsolete mitochondrial complex II deficiency
  Vascular dementia
  Dystonia
  Leigh syndrome
• UniProt ID: SDHF1_HUMAN
• Pfam ID: PF05347
• Sequence:
  MSRHSRLQRQVLSLYRDLLRAGRGKPGAEARVRAEFRQHAGLPRSDVLRIEYLYRRGRRQ
  LQLLRSGHATAMGAFVRPRAPTGEPGGVGCQPDDGDSPRNPHDSTGAPETRPDGR
• 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. Promotes maturation of the iron-sulfur protein subunit SDHB of the SDH catalytic dimer, protecting it from the deleterious effects of oxidants. May act together with SDHAF3. Contributes to iron-sulfur cluster incorporation into SDHB by binding to SDHB and recruiting the iron-sulfur transfer complex formed by HSC20, HSPA9 and ISCU through direct binding to HSC20.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Definitive	Genetic Variation	[1]
Mitochondrial complex II deficiency, nuclear type 1	DISJ424P	Definitive	Autosomal recessive	[2]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[3]
Obsolete mitochondrial complex II deficiency	DIS67XU0	Moderate	Autosomal recessive	[4]
Vascular dementia	DISVO82H	Disputed	Biomarker	[5]
Dystonia	DISJLFGW	Limited	Biomarker	[6]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[3]

11 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 Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[8]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[8]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[8]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[8]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[13]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Succinate dehydrogenase assembly factor 1, mitochondrial (SDHAF1).	[10]

References

• [1] Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J Med Genet. 2012 Sep;49(9):569-77. doi: 10.1136/jmedgenet-2012-101146.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] 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.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet. 2009 Jun;41(6):654-6. doi: 10.1038/ng.378. Epub 2009 May 24.
• [6] Complex II deficiency--a case report and review of the literature.Am J Med Genet A. 2013 Feb;161A(2):285-94. doi: 10.1002/ajmg.a.35714. Epub 2013 Jan 15.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.