Disease relevance of ETFDH

• We have expressed human ETF-QO in Sf9 insect cells using a baculovirus vector [1].
• Deficiencies in ETF or ETF-QO result in multiple acyl-CoA dehydrogenase deficiency, a human metabolic disease [2].
• Lipid-storage myopathy and respiratory insufficiency due to ETFQO mutations in a patient with late-onset multiple acyl-CoA dehydrogenation deficiency [3].
• MADD should be considered in the differential diagnosis of elevated alpha-fetoprotein and cystic renal disease [4].
• Detection of fetal or neonatal polycystic kidneys should alert the physician to the possibility of an associated lethal autosomal recessive inborn error of fatty acid metabolism known as multiple acyl-CoA-dehydrogenase defect (MADD) [5].

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

• The results demonstrate that this expression system provides sufficient amounts of human ETF-QO to enable crystallization and mechanistic investigations of the iron-sulphur flavoprotein [1].
• Sequence analysis of the unique Arabidopsis thaliana homologue of ETFQO revealed high similarity to the mammalian ETFQO protein [6].
• Melatonin prevents the free radical and MADD metabolic profiles induced by antituberculosis drugs in an animal model [14].
• Early diagnosis and treatment may change the natural history of MADD [17].
• The observation of simple Michaelis-Menten kinetic patterns and a single type of quinone-binding site, determined by fluorescence titrations of the protein with DBMIB and 6-(10-bromodecyl)ubiquinone, are consistent with one ubiquinone-binding site per ETF-QO monomer [18].

References