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Gene Review

ETFDH  -  electron-transferring-flavoprotein...

Homo sapiens

Synonyms: ETF dehydrogenase, ETF-QO, ETF-ubiquinone oxidoreductase, ETFQO, Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial, ...
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Disease relevance of ETFDH


High impact information on ETFDH

  • In mammals, electron-transfer flavoprotein:ubiquinone oxidoreductase (ETFQO) and electron-transfer flavoprotein (ETF) are functionally associated, and ETF accepts electrons from at least nine mitochondrial matrix flavoprotein dehydrogenases and transfers them to ubiquinone in the inner mitochondrial membrane [6].
  • Analysis of three independent insertional mutants of Arabidopsis ETFQO revealed a dramatic reduction in their ability to withstand extended darkness, resulting in senescence and death within 10 d after transfer, whereas wild-type plants remained viable for at least 15 d [6].
  • In addition, the mammalian ETF/ETFQO system plays a key role in beta-oxidation of fatty acids and catabolism of amino acids and choline [6].
  • In both cases, when ETF-QO is reduced to a two-electron reduced state (one electron at each redox center), the enzyme is primed to reduce UQ to ubiquinol via FAD [2].
  • First, electrons from the ETF flavin semiquinone may enter the ETF-QO flavin one by one, followed by rapid equilibration with the cluster [2].

Biological context of ETFDH

  • In agreement with these findings, mutational analysis of the ETF/ETFDH genes demonstrated an ETFB missense mutation 124T>C in exon 2 leading to replacement of cysteine-42 with arginine (C42R), and a 604_606AAG deletion in exon 6 in the ETFB gene resulting in the deletion of lysine-202 (K202del) [7].
  • Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency [8].
  • This indicates that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors like cellular temperature [8].
  • To examine whether these different clinical forms could be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, we have investigated the molecular genetic basis for disease development in nine patients representing the phenotypic spectrum of MADD [8].
  • Even minute amounts of residual ETF/ETFDH activity seem to be sufficient to prevent embryonic development of congenital anomalies giving rise to type II disease [8].

Anatomical context of ETFDH

  • These data suggest that the heterologously expressed ETF-QO is targeted to mitochondria and processed to the mature, catalytically active form [1].
  • The ETF-QO 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 [9].
  • Fibroblasts from two other patients with severe GA II had normal levels of ETF-QO activity and antigen but were deficient in immunoreactive ETF [10].
  • EPR of the same membranes showed a marked decrease in the ETF dehydrogenase signal [11].
  • Our results suggest that intermediates of unsaturated fatty acid oxidation that accumulate as a consequence of MCADD, MADD and VLCADD are transported to the endoplasmic reticulum for esterification into neutral glycerolipids [12].

Associations of ETFDH with chemical compounds

  • Multiple acyl-CoA-dehydrogenase deficiency (MADD) or glutaric aciduria type II (GAII) are a group of metabolic disorders due to deficiency of either electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxidoreductase (ETF-QO) [7].
  • He had glutaric aciduria type II, and his cultured fibroblasts contained normal activity of four different acyl CoA dehydrogenases, but there was deficiency of electron transfer flavoprotein:ubiquinone oxidoreductase (ETF-QO) [13].
  • We also conclude that free radicals leading to clinical symptoms associated with an MADD metabolic profile induced by anti-TB treatment could be alleviated by melatonin intervention [14].
  • These results indicate that the 4'-hydroxyl-N(1) hydrogen bond plays a major role in the stabilization of the anionic semiquinone and anionic hydroquinone oxidation states of ETF and that this hydrogen bond may provide a pathway for electron transfer between the ETF flavin and the flavin of ETF-QO [15].
  • Secondary carnitine deficiency in a patient with glutaric acidaemia type II, due to deficient ETF-dehydrogenase activity, is described [16].

Analytical, diagnostic and therapeutic context of ETFDH


  1. Expression of human electron transfer flavoprotein-ubiquinone oxidoreductase from a baculovirus vector: kinetic and spectral characterization of the human protein. Simkovic, M., Degala, G.D., Eaton, S.S., Frerman, F.E. Biochem. J. (2002) [Pubmed]
  2. Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool. Zhang, J., Frerman, F.E., Kim, J.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. Lipid-storage myopathy and respiratory insufficiency due to ETFQO mutations in a patient with late-onset multiple acyl-CoA dehydrogenation deficiency. Olsen, R.K., Pourfarzam, M., Morris, A.A., Dias, R.C., Knudsen, I., Andresen, B.S., Gregersen, N., Olpin, S.E. J. Inherit. Metab. Dis. (2004) [Pubmed]
  4. Prenatal diagnosis of multiple acyl-CoA dehydrogenase deficiency: association with elevated alpha-fetoprotein and cystic renal changes. Chisholm, C.A., Vavelidis, F., Lovell, M.A., Sweetman, L., Roe, C.R., Roe, D.S., Frerman, F.E., Wilson, W.G. Prenat. Diagn. (2001) [Pubmed]
  5. Fetal polycystic kidney disease associated with glutaric aciduria type II: an inborn error of energy metabolism. Whitfield, J., Hurst, D., Bennett, M.J., Sherwood, W.G., Hogg, R., Gonsoulin, W. American journal of perinatology. (1996) [Pubmed]
  6. The critical role of Arabidopsis electron-transfer flavoprotein:ubiquinone oxidoreductase during dark-induced starvation. Ishizaki, K., Larson, T.R., Schauer, N., Fernie, A.R., Graham, I.A., Leaver, C.J. Plant Cell (2005) [Pubmed]
  7. Late-onset form of beta-electron transfer flavoprotein deficiency. Curcoy, A., Olsen, R.K., Ribes, A., Trenchs, V., Vilaseca, M.A., Campistol, J., Osorio, J.H., Andresen, B.S., Gregersen, N. Mol. Genet. Metab. (2003) [Pubmed]
  8. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Olsen, R.K., Andresen, B.S., Christensen, E., Bross, P., Skovby, F., Gregersen, N. Hum. Mutat. (2003) [Pubmed]
  9. Molecular cloning and expression of a cDNA encoding human electron transfer flavoprotein-ubiquinone oxidoreductase. Goodman, S.I., Axtell, K.M., Bindoff, L.A., Beard, S.E., Gill, R.E., Frerman, F.E. Eur. J. Biochem. (1994) [Pubmed]
  10. Deficiency of electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase in glutaric acidemia type II fibroblasts. Frerman, F.E., Goodman, S.I. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  11. Glutaric acidaemia type II (multiple acyl-CoA dehydrogenation deficiency). Goodman, S.I., Frerman, F.E. J. Inherit. Metab. Dis. (1984) [Pubmed]
  12. Intermediates of unsaturated fatty acid oxidation are incorporated in triglycerides but not in phospholipids in tissues from patients with mitochondrial beta-oxidation defects. Onkenhout, W., Venizelos, V., Scholte, H.R., De Klerk, J.B., Poorthuis, B.J. J. Inherit. Metab. Dis. (2001) [Pubmed]
  13. Systemic carnitine deficiency due to lack of electron transfer flavoprotein:ubiquinone oxidoreductase. Di Donato, S., Frerman, F.E., Rimoldi, M., Rinaldo, P., Taroni, F., Wiesmann, U.N. Neurology (1986) [Pubmed]
  14. Melatonin prevents the free radical and MADD metabolic profiles induced by antituberculosis drugs in an animal model. Loots, d.u. .T., Wiid, I.J., Page, B.J., Mienie, L.J., van Helden, P.D. J. Pineal Res. (2005) [Pubmed]
  15. The intraflavin hydrogen bond in human electron transfer flavoprotein modulates redox potentials and may participate in electron transfer. Dwyer, T.M., Mortl, S., Kemter, K., Bacher, A., Fauq, A., Frerman, F.E. Biochemistry (1999) [Pubmed]
  16. The importance of recognizing secondary carnitine deficiency in organic acidaemias: case report in glutaric acidaemia type II. Mandel, H., Africk, D., Blitzer, M., Shapira, E. J. Inherit. Metab. Dis. (1988) [Pubmed]
  17. Multiple acyl-CoA-dehydrogenase deficiency (MADD): use of acylcarnitines and fatty acids to monitor the response to dietary treatment. Abdenur, J.E., Chamoles, N.A., Schenone, A.B., Jorge, L., Guinle, A., Bernard, C., Levandovskiy, V., Fusta, M., Lavorgna, S. Pediatr. Res. (2001) [Pubmed]
  18. Alternative quinone substrates and inhibitors of human electron-transfer flavoprotein-ubiquinone oxidoreductase. Simkovic, M., Frerman, F.E. Biochem. J. (2004) [Pubmed]
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