Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFG5777)

• DOT Name: NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11)
• Synonyms: Complex I-ESSS; CI-ESSS; NADH-ubiquinone oxidoreductase ESSS subunit; Neuronal protein 17.3; Np17.3; p17.3
• Gene Name: NDUFB11
• Related Disease:
  Mitochondrial disease
  Leber hereditary optic neuropathy
  Linear skin defects with multiple congenital anomalies 1
  Linear skin defects with multiple congenital anomalies 3
  Mitochondrial complex 1 deficiency, nuclear type 30
  Mitochondrial complex I deficiency
  Mitochondrial encephalomyopathy
  Lactic acidosis
  Sideroblastic anemia
  X-linked sideroblastic anemia 1
  Linear skin defects with multiple congenital anomalies
  Neuroblastoma
• UniProt ID: NDUBB_HUMAN
• PDB ID: 5XTC; 5XTD; 5XTH; 5XTI
• Pfam ID: PF10183
• Sequence:
  MAAGLFGLSARRLLAAAATRGLPAARVRWESSFSRTVVAPSAVAGKRPPEPTTPWQEDPE
  PEDENLYEKNPDSHGYDKDPVLDVWNMRLVFFFGVSIILVLGSTFVAYLPDYRMKEWSRR
  EAERLVKYREANGLPIMESNCFDPSKIQLPEDE
• Function: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis. Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Retrograde endocan.binoid sig.ling (hsa04723)
  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:
  Complex I biogenesis (R-HSA-6799198)
  Respiratory electron transport (R-HSA-611105)
• BioCyc Pathway: MetaCyc:HS14193-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	X-linked	[1]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[2]
Linear skin defects with multiple congenital anomalies 1	DISNYKBT	Strong	X-linked dominant	[3]
Linear skin defects with multiple congenital anomalies 3	DISIL4GT	Strong	X-linked	[3]
Mitochondrial complex 1 deficiency, nuclear type 30	DISH91ZM	Strong	X-linked	[4]
Mitochondrial complex I deficiency	DIS13M7V	Strong	Genetic Variation	[5]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Biomarker	[6]
Lactic acidosis	DISZI1ZK	moderate	Genetic Variation	[4]
Sideroblastic anemia	DIS4F3X1	moderate	Genetic Variation	[4]
X-linked sideroblastic anemia 1	DISWBQC7	moderate	Biomarker	[7]
Linear skin defects with multiple congenital anomalies	DIS5BT4L	Supportive	X-linked	[3]
Neuroblastoma	DISVZBI4	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[16]
[3H]cAMP	DMZRQU7	Investigative	[3H]cAMP increases the phosphorylation of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial (NDUFB11).	[17]

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] The NDUFB11 gene is not a modifier in Leber hereditary optic neuropathy.Biochem Biophys Res Commun. 2007 Mar 30;355(1):181-7. doi: 10.1016/j.bbrc.2007.01.140. Epub 2007 Feb 2.
• [3] Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome. Am J Hum Genet. 2015 Apr 2;96(4):640-50. doi: 10.1016/j.ajhg.2015.02.002. Epub 2015 Mar 12.
• [4] A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia. Clin Genet. 2017 Mar;91(3):441-447. doi: 10.1111/cge.12790. Epub 2016 May 25.
• [5] A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan 7;12(1):e1005679. doi: 10.1371/journal.pgen.1005679. eCollection 2016 Jan.
• [6] X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann Neurol. 2007 Jan;61(1):73-83. doi: 10.1002/ana.21036.
• [7] A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia.Blood. 2016 Oct 13;128(15):1913-1917. doi: 10.1182/blood-2016-05-719062. Epub 2016 Aug 3.
• [8] The mechanism of alternative splicing of the X-linked NDUFB11 gene of the respiratory chain complex I, impact of rotenone treatment in neuroblastoma cells.Biochim Biophys Acta. 2013 Feb;1829(2):211-8. doi: 10.1016/j.bbagrm.2012.12.001. Epub 2012 Dec 12.
• [9] 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.
• [10] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [11] 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.
• [12] 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.
• [13] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] 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.
• [17] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [18] Adenosine 3',5'-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors. Toxicol Appl Pharmacol. 2008 Jan 1;226(1):94-106. doi: 10.1016/j.taap.2007.08.015. Epub 2007 Aug 25.