Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0UG9H5)

• DOT Name: Succinate dehydrogenase assembly factor 2, mitochondrial (SDHAF2)
• Synonyms: SDH assembly factor 2; SDHAF2
• Gene Name: SDHAF2
• Related Disease:
  Hereditary pheochromocytoma-paraganglioma
  Paragangliomas 2
  Breast cancer
  Breast carcinoma
  Hereditary neoplastic syndrome
  Lung cancer
  Lung carcinoma
  Neoplasm
  Neuroendocrine neoplasm
  Non-small-cell lung cancer
  Paraganglioma
  Pheochromocytoma
  Primary hyperparathyroidism
  Prostate carcinoma
  Spinocerebellar ataxia type 5
  Von hippel-lindau disease
  Wilson disease
  Mitochondrial disease
  Clear cell renal carcinoma
  Glioma
  Neuroblastoma
• UniProt ID: SDHF2_HUMAN
• PDB ID: 6VAX
• Pfam ID: PF03937
• Sequence:
  MAVSTVFSTSSLMLALSRHSLLSPLLSVTSFRRFYRGDSPTDSQKDMIEIPLPPWQERTD
  ESIETKRARLLYESRKRGMLENCILLSLFAKEHLQHMTEKQLNLYDRLINEPSNDWDIYY
  WATEAKPAPEIFENEVMALLRDFAKNKNKEQRLRAPDLEYLFEKPR
• 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. Required for flavinylation (covalent attachment of FAD) of the flavoprotein subunit SDHA of the SDH catalytic dimer.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary pheochromocytoma-paraganglioma	DISP9K7L	Definitive	Autosomal dominant	[1]
Paragangliomas 2	DIS19SG7	Definitive	Autosomal dominant	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Hereditary neoplastic syndrome	DISGXLG5	Strong	CausalMutation	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neuroendocrine neoplasm	DISNPLOO	Strong	Genetic Variation	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Paraganglioma	DIS2XXH5	Strong	Genetic Variation	[7]
Pheochromocytoma	DIS56IFV	Strong	Genetic Variation	[8]
Primary hyperparathyroidism	DISB4U1Q	Strong	Genetic Variation	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[9]
Spinocerebellar ataxia type 5	DISPYXJ0	Strong	Genetic Variation	[10]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[11]
Wilson disease	DISVS9H7	Strong	Biomarker	[12]
Mitochondrial disease	DISKAHA3	moderate	Biomarker	[13]
Clear cell renal carcinoma	DISBXRFJ	Limited	Genetic Variation	[14]
Glioma	DIS5RPEH	Limited	Biomarker	[15]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Succinate dehydrogenase assembly factor 2, mitochondrial (SDHAF2).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Succinate dehydrogenase assembly factor 2, mitochondrial (SDHAF2).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Succinate dehydrogenase assembly factor 2, mitochondrial (SDHAF2).	[19]

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 affects the methylation of Succinate dehydrogenase assembly factor 2, mitochondrial (SDHAF2).	[18]

References

• [1] 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.
• [2] Genetic aspects of nonchromaffin paraganglioma. Hum Genet. 1982;60(4):305-9. doi: 10.1007/BF00569208.
• [3] The Assembly Factor SDHAF2 Is Dispensable for Flavination of the Catalytic Subunit of Mitochondrial Complex II in Breast Cancer Cells.J Biol Chem. 2016 Oct 7;291(41):21414-21420. doi: 10.1074/jbc.C116.755017. Epub 2016 Sep 1.
• [4] Loss of maternal chromosome 11 is a signature event in SDHAF2, SDHD, and VHL-related paragangliomas, but less significant in SDHB-related paragangliomas.Oncotarget. 2017 Feb 28;8(9):14525-14536. doi: 10.18632/oncotarget.14649.
• [5] SDH5 Depletion Enhances Radiosensitivity by Regulating p53: A New Method for Noninvasive Prediction of Radiotherapy Response.Theranostics. 2019 Aug 14;9(22):6380-6395. doi: 10.7150/thno.34443. eCollection 2019.
• [6] Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism.Endocrine. 2010 Dec;38(3):397-401. doi: 10.1007/s12020-010-9399-0. Epub 2010 Oct 23.
• [7] Malignant Intrarenal/Renal Pelvis Paraganglioma with Co-Occurring SDHB and ATRX Mutations.Endocr Pathol. 2019 Dec;30(4):270-275. doi: 10.1007/s12022-019-09594-1.
• [8] Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.JAMA Oncol. 2017 Sep 1;3(9):1204-1212. doi: 10.1001/jamaoncol.2017.0223.
• [9] In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells.Prostate. 2005 Jun 15;64(1):20-8. doi: 10.1002/pros.20209.
• [10] A 3-Mb sequence-ready contig map encompassing the multiple disease gene cluster on chromosome 11q13.1-q13.3.DNA Res. 1997 Aug 31;4(4):281-9. doi: 10.1093/dnares/4.4.281.
• [11] Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas.J Clin Endocrinol Metab. 2010 Mar;95(3):1274-8. doi: 10.1210/jc.2009-2170. Epub 2009 Nov 13.
• [12] The early molecular processes underlying the neurological manifestations of an animal model of Wilson's disease.Metallomics. 2013 May;5(5):532-40. doi: 10.1039/c3mt20243g. Epub 2013 Mar 21.
• [13] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [14] SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis.Free Radic Biol Med. 2019 Apr;134:458-467. doi: 10.1016/j.freeradbiomed.2019.01.030. Epub 2019 Jan 29.
• [15] Valproate robustly enhances AP-1 mediated gene expression.Brain Res Mol Brain Res. 1999 Jan 22;64(1):52-8. doi: 10.1016/s0169-328x(98)00303-9.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] 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.
• [18] 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.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.