Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYZ8XRH)

• DOT Name: Succinate dehydrogenase cytochrome b small subunit, mitochondrial (SDHD)
• Synonyms: CybS; CII-4; QPs3; Succinate dehydrogenase complex subunit D; Succinate-ubiquinone oxidoreductase cytochrome b small subunit; Succinate-ubiquinone reductase membrane anchor subunit
• Gene Name: SDHD
• Related Disease:
  Hereditary pheochromocytoma-paraganglioma
  Paragangliomas 1
  Carney-Stratakis syndrome
  Mitochondrial complex II deficiency, nuclear type 1
  Obsolete mitochondrial complex II deficiency
  Renal cell carcinoma
  Cowden disease
  Mitochondrial disease
• UniProt ID: DHSD_HUMAN
• PDB ID: 8GS8
• Pfam ID: PF05328
• Sequence:
  MAVLWRLSAVCGALGGRALLLRTPVVRPAHISAFLQDRPIPEWCGVQHIHLSPSHHSGSK
  AASLHWTSERVVSVLLLGLLPAAYLNPCSAMDYSLAAALTLHGHWGLGQVVTDYVHGDAL
  QKAAKAGLLALSALTFAGLCYFNYHDVGICKAVAMLWKL
• Function: Membrane-anchoring subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  Thermogenesis (hsa04714)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Citric acid cycle (TCA cycle) (R-HSA-71403)
  Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:ENSG00000150781-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 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 1	DISZ7KOC	Definitive	Autosomal dominant	[2]
Carney-Stratakis syndrome	DISP3P3F	Strong	Autosomal dominant	[3]
Mitochondrial complex II deficiency, nuclear type 1	DISJ424P	Strong	Autosomal recessive	[4]
Obsolete mitochondrial complex II deficiency	DIS67XU0	Moderate	Autosomal recessive	[2]
Renal cell carcinoma	DISQZ2X8	Moderate	Autosomal dominant	[3]
Cowden disease	DISMYKCE	Supportive	Autosomal dominant	[5]
Mitochondrial disease	DISKAHA3	Limited	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Succinate dehydrogenase cytochrome b small subunit, mitochondrial (SDHD).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Succinate dehydrogenase cytochrome b small subunit, mitochondrial (SDHD).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Succinate dehydrogenase cytochrome b small subunit, mitochondrial (SDHD).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Succinate dehydrogenase cytochrome b small subunit, mitochondrial (SDHD).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Succinate dehydrogenase cytochrome b small subunit, mitochondrial (SDHD).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Succinate dehydrogenase cytochrome b small subunit, mitochondrial (SDHD).	[11]

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] 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.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family. Eur J Hum Genet. 2010 Jan;18(1):62-6. doi: 10.1038/ejhg.2009.112.
• [5] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [10] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.