Difference between revisions of "ETFDH"

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'''Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''ETFDH'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: ETFDH electron-transferring-flavoprotein dehydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2110| accessdate = }}</ref>
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'''Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''ETFDH'' [[gene]]. This gene encodes a component of the [[Electron_transport_chain#In_mitochondria|electron-transfer system]] in [[mitochondrion|mitochondria]] and is essential for [[electron transfer]] from a number of mitochondrial [[Flavin_group|flavin]]-containing [[dehydrogenase]]s to the main respiratory chain.<ref name="entrez">{{cite web | title = Entrez Gene: ETFDH electron-transferring-flavoprotein dehydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2110| access-date = }}</ref>
  
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== Function ==
{{PBB_Summary
 
| section_title =  
 
| summary_text = Electron-transferring-flavoprotein dehydrogenase in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein which is located in the mitochondrial matrix and reduces ubiquinone in the mitochondrial membrane.  The protein is synthesized as a 67-kDa precursor which is targeted to mitochondria and processed in a single step to a 64-kDa mature form located in the mitochondrial membrane.  Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with type II  glutaricacidemia.<ref name="entrez">{{cite web | title = Entrez Gene: ETFDH electron-transferring-flavoprotein dehydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2110| accessdate = }}</ref>
 
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==References==
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Electron-transferring-flavoprotein dehydrogenase in the [[inner mitochondrial membrane]] accepts electrons from [[Electron-transferring_flavoprotein|electron-transfer flavoprotein]] which is located in the [[mitochondrial matrix]] and [[Reduction_(chemistry)|reduces]] [[ubiquinone]] in the mitochondrial membrane. Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with [[Glutaric acidemia type 2|type II glutaric aciduria]].<ref name="entrez">{{cite web | title = Entrez Gene: ETFDH electron-transferring-flavoprotein dehydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2110| access-date = }}</ref>
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==Further reading==
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== Structure ==
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The ''ETFDH'' gene is located on the q arm of [[chromosome 4]] in position 32.1 and has 13 [[exon]]s spanning 36,613 base pairs.<ref>{{cite journal | vauthors = Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N | title = Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency | journal = Human Mutation | volume = 22 | issue = 1 | pages = 12–23 | date = July 2003 | pmid = 12815589 | doi = 10.1002/humu.10226 }}</ref><ref name=":1">{{OMIM|231675|Electron transfer flavoprotein dehydrogenase; ETFDH}}</ref> The protein is [[Protein_biosynthesis#Events_during_or_following_protein_translation|synthesized]] as a 67-kDa [[Protein precursor|precursor]] which is [[Protein subcellular localization prediction|targeted]] to mitochondria and processed in a single step to a 64-kDa mature form located in the mitochondrial membrane.<ref name = "entrez"/> This 64-kDA mature form is a monomer [[integral membrane protein|integrated]] into the mitochondrial inner membrane, containing a [[Iron–sulfur_protein#4Fe–4S_clusters|4Fe-4S]] cluster and 1 molecule of [[Flavin_adenine_dinucleotide|FAD]].<ref name=":1" />
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== Function ==
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This enzyme, along with electron transfer flavoprotein (ETF), is required for electron transfer from more than 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chains.<ref name=":1" /> It accepts electrons from ETF and reduces ubiquinone.<ref name=":0" /><ref name=":3" />
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== Clinical Significance ==
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[[Mutation]]s in the ''ETFDH'' can cause glutaric aciduria 2C (GA2C), an [[Genetic_disorder#Autosomal_recessive|autosomal recessively inherited]] disorder of [[fatty acid]], [[amino acid]], and [[choline]] metabolism. It is characterized by multiple [[Acyl_CoA_dehydrogenase#Deficiencies_linked_to_metabolic_disease_in_animals|acyl-CoA dehydrogenase deficiencies]] resulting in large excretion not only of [[glutaric acid]], but also of [[lactic acid|lactic]], [[ethylmalonic acid|ethylmalonic]], [[butyric acid|butyric]], [[isobutyric acid|isobutyric]], [[2-methylbutyric acid|2-methyl-butyric]], and [[isovaleric acid]]s.<ref name=":0">{{Cite web|url=https://www.uniprot.org/uniprot/Q16134|title= ETFDH - Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial precursor - Homo sapiens (Human) - STXBP1 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-29}}{{CC-notice|cc=by4}}</ref><ref name=":3">{{cite journal | vauthors =  | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158-D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 | url = https://doi.org/10.1093/nar/gkw1099 }}</ref>
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A c.250G>A (p.Ala84Thr) mutation, the most common mutation in the ''ETFDH'' gene, causes increased production of [[reactive oxygen species]] (ROS) and shortened [[neurite]]s in cells [[gene expression|expressing]] this mutant compared to [[wild type]] cells. [[Suberic acid]], an accumulated [[Metabolic_intermediate|intermediate]] [[metabolite]] in dehydrogenase deficiency, can significantly impair neurite outgrowth in [[Neural stem cell|NSC34 cells]]. This shortening of neurites can be restored by [[riboflavin]], [[carnitine]], or [[Coenzyme Q10]] supplements.<ref>{{cite journal | vauthors = Liang WC, Lin YF, Liu TY, Chang SC, Chen BH, Nishino I, Jong YJ | title = Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors | journal = Muscle & Nerve | volume = 56 | issue = 3 | pages = 479–485 | date = September 2017 | pmid = 27935074 | doi = 10.1002/mus.25501 }}</ref>
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== Interactions ==
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The encoded protein [[protein-protein interactions|interacts]] with [[MYH7B]], [[LINC00174]], [[LINC00574]], [[Homeobox protein goosecoid-2]], [[AIRE]], [[OTX1]], [[Keratin-associated protein 13-2]], [[Keratin-associated protein 11-1]], [[TRIM69]], [[Zinc finger protein 581]], and [[COX6B1]].<ref>{{Cite web|url=https://www.ebi.ac.uk/intact/interactors/id:Q16134*|title=ETFDH interactions|last=IntAct|website=www.ebi.ac.uk|language=en|access-date=2018-09-05}}</ref>
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== References ==
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== Further reading ==
 
{{refbegin | 2}}
 
{{refbegin | 2}}
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* {{cite journal | vauthors = Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM | title = Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle | journal = Journal of Inherited Metabolic Disease | volume = 33 Suppl 3 | pages = S481-7 | date = December 2010 | pmid = 21088898 | doi = 10.1007/s10545-010-9246-8 }}
| citations =  
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* {{cite journal | vauthors = Wen B, Li D, Li W, Zhao Y, Yan C | title = Multiple acyl-CoA dehydrogenation deficiency as decreased acyl-carnitine profile in serum | journal = Neurological Sciences | volume = 36 | issue = 6 | pages = 853–9 | date = June 2015 | pmid = 25827849 | doi = 10.1007/s10072-015-2197-y }}
*{{cite journal | vauthors=Olsen RK, Olpin SE, Andresen BS |title=ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. |journal=Brain |volume=130 |issue= Pt 8 |pages= 2045–54 |year= 2007 |pmid= 17584774 |doi= 10.1093/brain/awm135 |display-authors=etal}}
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* {{cite journal | vauthors = Whitaker CH, Felice KJ, Silvers D, Wu Q | title = Fulminant lipid storage myopathy due to multiple acyl-coenzyme a dehydrogenase deficiency | journal = Muscle & Nerve | volume = 52 | issue = 2 | pages = 289–93 | date = August 2015 | pmid = 25556768 | doi = 10.1002/mus.24552 }}
*{{cite journal | vauthors=Gempel K, Topaloglu H, Talim B |title=The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene. |journal=Brain |volume=130 |issue= Pt 8 |pages= 2037–44 |year= 2007 |pmid= 17412732 |doi= 10.1093/brain/awm054 |display-authors=etal}}
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* {{cite journal | vauthors = Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, Andersen O, Oldfors A, Holme E, Gregersen N, Turnbull DM, Morris AA | title = ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency | journal = Brain | volume = 130 | issue = Pt 8 | pages = 2045–54 | date = August 2007 | pmid = 17584774 | doi = 10.1093/brain/awm135 }}
*{{cite journal | vauthors=Kimura K, Wakamatsu A, Suzuki Y |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. |journal=Genome Res. |volume=16 |issue= 1 |pages= 55–65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406  | pmc=1356129 |display-authors=etal}}
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* {{cite journal | vauthors = Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BG, Hans VH, Pálmafy B, Kale G, Tokatli A, Quinzii C, Hirano M, Naini A, DiMauro S, Prokisch H, Lochmüller H, Horvath R | title = The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene | journal = Brain | volume = 130 | issue = Pt 8 | pages = 2037–44 | date = August 2007 | pmid = 17412732 | pmc = 4345103 | doi = 10.1093/brain/awm054 }}
*{{cite journal | vauthors=Gerhard DS, Wagner L, Feingold EA |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504  | pmc=528928 |display-authors=etal}}
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* {{cite journal | vauthors = Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N | title = Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency | journal = Human Mutation | volume = 22 | issue = 1 | pages = 12–23 | date = July 2003 | pmid = 12815589 | doi = 10.1002/humu.10226 }}
*{{cite journal | vauthors=Olsen RK, Andresen BS, Christensen E |title=Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. |journal=Hum. Mutat. |volume=22 |issue= 1 |pages= 12–23 |year= 2003 |pmid= 12815589 |doi= 10.1002/humu.10226 |display-authors=etal}}
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* {{cite journal | vauthors = Goodman SI, Binard RJ, Woontner MR, Frerman FE | title = Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene | journal = Molecular Genetics and Metabolism | volume = 77 | issue = 1-2 | pages = 86–90 | year = 2003 | pmid = 12359134 | doi = 10.1016/S1096-7192(02)00138-5 }}
*{{cite journal | vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 |display-authors=etal}}
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* {{cite journal | vauthors = Simkovic M, Degala GD, Eaton SS, Frerman FE | title = Expression of human electron transfer flavoprotein-ubiquinone oxidoreductase from a baculovirus vector: kinetic and spectral characterization of the human protein | journal = The Biochemical Journal | volume = 364 | issue = Pt 3 | pages = 659–67 | date = June 2002 | pmid = 12049629 | pmc = 1222614 | doi = 10.1042/BJ20020042 }}
*{{cite journal  | vauthors=Goodman SI, Binard RJ, Woontner MR, Frerman FE |title=Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene. |journal=Mol. Genet. Metab. |volume=77 |issue= 1–2 |pages= 86–90 |year= 2003 |pmid= 12359134 |doi=10.1016/S1096-7192(02)00138-5 }}
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* {{cite journal | vauthors = White RA, Dowler LL, Angeloni SV, Koeller DM | title = Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and 13: the mouse homologs of genes responsible for glutaric acidemia type II in human | journal = Genomics | volume = 33 | issue = 1 | pages = 131–4 | date = April 1996 | pmid = 8617498 | doi = 10.1006/geno.1996.0170 }}
*{{cite journal | vauthors=Simkovic M, Degala GD, Eaton SS, Frerman FE |title=Expression of human electron transfer flavoprotein-ubiquinone oxidoreductase from a baculovirus vector: kinetic and spectral characterization of the human protein |journal=Biochem. J. |volume=364 |issue= Pt 3 |pages= 659–67 |year= 2002 |pmid= 12049629 |doi= 10.1042/BJ20020042 | pmc=1222614 }}
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* {{cite journal | vauthors = Goodman SI, Axtell KM, Bindoff LA, Beard SE, Gill RE, Frerman FE | title = Molecular cloning and expression of a cDNA encoding human electron transfer flavoprotein-ubiquinone oxidoreductase | journal = European Journal of Biochemistry | volume = 219 | issue = 1-2 | pages = 277–86 | date = January 1994 | pmid = 8306995 | doi = 10.1111/j.1432-1033.1994.tb19939.x }}
*{{cite journal | vauthors=White RA, Dowler LL, Angeloni SV, Koeller DM |title=Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and 13: the mouse homologs of genes responsible for glutaric acidemia type II in human |journal=Genomics |volume=33 |issue= 1 |pages= 131–4 |year= 1996 |pmid= 8617498 |doi= 10.1006/geno.1996.0170 }}
 
*{{cite journal | vauthors=Goodman SI, Axtell KM, Bindoff LA |title=Molecular cloning and expression of a cDNA encoding human electron transfer flavoprotein-ubiquinone oxidoreductase |journal=Eur. J. Biochem. |volume=219 |issue= 1–2 |pages= 277–86 |year= 1994 |pmid= 8306995 |doi=10.1111/j.1432-1033.1994.tb19939.x |display-authors=etal}}
 
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Revision as of 02:50, 7 September 2018

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Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.[1]

Function

Electron-transferring-flavoprotein dehydrogenase in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein which is located in the mitochondrial matrix and reduces ubiquinone in the mitochondrial membrane. Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with type II glutaric aciduria.[1]

Structure

The ETFDH gene is located on the q arm of chromosome 4 in position 32.1 and has 13 exons spanning 36,613 base pairs.[2][3] The protein is synthesized as a 67-kDa precursor which is targeted to mitochondria and processed in a single step to a 64-kDa mature form located in the mitochondrial membrane.[1] This 64-kDA mature form is a monomer integrated into the mitochondrial inner membrane, containing a 4Fe-4S cluster and 1 molecule of FAD.[3]

Function

This enzyme, along with electron transfer flavoprotein (ETF), is required for electron transfer from more than 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chains.[3] It accepts electrons from ETF and reduces ubiquinone.[4][5]

Clinical Significance

Mutations in the ETFDH can cause glutaric aciduria 2C (GA2C), an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It is characterized by multiple acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids.[4][5]

A c.250G>A (p.Ala84Thr) mutation, the most common mutation in the ETFDH gene, causes increased production of reactive oxygen species (ROS) and shortened neurites in cells expressing this mutant compared to wild type cells. Suberic acid, an accumulated intermediate metabolite in dehydrogenase deficiency, can significantly impair neurite outgrowth in NSC34 cells. This shortening of neurites can be restored by riboflavin, carnitine, or Coenzyme Q10 supplements.[6]

Interactions

The encoded protein interacts with MYH7B, LINC00174, LINC00574, Homeobox protein goosecoid-2, AIRE, OTX1, Keratin-associated protein 13-2, Keratin-associated protein 11-1, TRIM69, Zinc finger protein 581, and COX6B1.[7]

References

  1. 1.0 1.1 1.2 "Entrez Gene: ETFDH electron-transferring-flavoprotein dehydrogenase".
  2. Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N (July 2003). "Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency". Human Mutation. 22 (1): 12–23. doi:10.1002/humu.10226. PMID 12815589.
  3. 3.0 3.1 3.2 Online Mendelian Inheritance in Man (OMIM) Electron transfer flavoprotein dehydrogenase; ETFDH -231675
  4. 4.0 4.1 "ETFDH - Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial precursor - Homo sapiens (Human) - STXBP1 gene & protein". www.uniprot.org. Retrieved 2018-08-29.80px This article incorporates text available under the CC BY 4.0 license.
  5. 5.0 5.1 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
  6. Liang WC, Lin YF, Liu TY, Chang SC, Chen BH, Nishino I, Jong YJ (September 2017). "Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors". Muscle & Nerve. 56 (3): 479–485. doi:10.1002/mus.25501. PMID 27935074.
  7. IntAct. "ETFDH interactions". www.ebi.ac.uk. Retrieved 2018-09-05.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.