The rate constant of the first electron transfer reaction is several fold faster than that of the second electron transfer reaction and therefore the FAD moiety in ETF is thought to be stabilized as a semiflavin (Hall & Lambeth, 1980; Ramsay et al., 1987). ETF in turn is reoxidized by ETFDH, which channels electrons from its FAD cofactor to coenzyme Q of complex III or the electron transport chain. An example is the fermentation of glutamate via 3-methyl-asparate by the closely related anaerobic bacteria Clostridium tetani, Clostridium tetanomorphum, and to Elevated serum creatine kinase is typical, but myoglobinuria is rare (14). ETC contains a number of Intermediate Carriers which carry the electrons. electron-transferring-flavoprotein dehydrogenase, Electron-transferring-flavoprotein dehydrogenase, "Three-dimensional structure of human electron transfer flavoprotein to 2.1-A resolution", Pfam entry for Electron transfer flavoprotein domain, Pfam entry for Electron transfer flavoprotein FAD-binding domain, https://en.wikipedia.org/w/index.php?title=Electron-transferring_flavoprotein&oldid=909475508, Creative Commons Attribution-ShareAlike License, This page was last edited on 5 August 2019, at 17:42. Electron Transport Chain (ETC) All the enzyme-catalyzed steps in the oxidative degradation of carbohydrates, fats and amino acids in aerobic cells converge into electron transport and oxidative phosphorylation, the final Since defects in these two proteins results in an inability to reoxidize the primary ACADs, derangements in all affected pathways occur and lead to a complex and variable accumulation of metabolites, including glutaric acid, ethylmalonic, butyric, isobutyric, 2-methylbutyric, and isovaleric acids [7]. Specific mutations in ETFDH have been associated with both riboflavin-responsive MADD and a myopathic form of CoQ10 deficiency [122–124]. Carnitine severs two purposes here: one, it is required to maximize accumulation of palmitoylcarnitine inside the mitochondria; and two, it supports high flux through β-oxidation by forming acetylcarnitine from the excess acetyl-CoA that accumulates as an end product (Perevoshchikova et al., 2013). A flavoprotein is one of many proteins present in human and animal cellular structure. Flavoproteins are involved in the electron transport chain and change their fluorescence according to the cellular redox state. Diagnosis: A diagnosis of MADD can be made through blood acylcarnitine profiling and characterization of urine organic acids. The A270/A436 ratio is then determined. Flavoprotein autofluorescence is an activity dependent intrinsic signal. The resin is packed into a Pharmacia (Piscataway, NJ) XK 50/20 column and washed with 1.2 to 1.5 liters of 10 mM potassium phosphate dibasic (unbuffered) at 10 ml/min, using a low-pressure chromatography system. 3 When flavoprotein transfers electrons directly to oxveen. Ingrid Tein, in Neuromuscular Disorders of Infancy, Childhood, and Adolescence (Second Edition), 2015, Certain cases of the multiple acyl-CoA dehydrogenase deficiencies (e.g. In intact cardiomyocytes, we followed the dynamics of electron fluxes along specific sites of the electron transport chain (ETC) by simultaneous detection of NAD(H)P and flavoprotein (FP) fluorescence intensities using a laser Thus it has been suggested that long-term therapy for ETFDH deficiency should include both coenzyme Q10 and riboflavin [126]. Lactic acid and ammonia may be secondarily elevated, and hypoglycemia may be present. Mutation in ETFs can lead to deficiency of passing reducing equivalent of FADH2 to electron transport chain, causing Glutaric acidemia type 2, electron transfer flavoprotein (etf) from paracoccus denitrificans. Typical patients with GA II exhibit neonatal acidosis and urinary excretion of glutaric, ethylmalonic, isovaleric, isobutyric, 2-methyl-butyric, saturated and unsaturated dicarboxylic acids and sarcosine. Sixty grams of Whatman (Clifton, NJ) DE52 (DEAE-cellulose) resin is freshly prepared for each experiment by rinsing the resin three times with 4 liters of H2O, and then equilibrating it overnight in 100 ml of 0.5 M potassium phosphate dibasic (unbuffered). Freshly harvested pig liver (500–600 g) is cut into small pieces, washed with ice-cold phosphate-buffered saline (pH 7.4), and homogenized in a blender with 50 mM KPO4 (pH 8.0), 1 mM EDTA, 2.5% (v/v) glycerol, and 250 mM sucrose. However, even those with truncating mutations have some residual FADS activity, which is attributed to the expression of alternative FADS isoforms encoding only the FADS domain.120, A. El-Gharbawy, J. Vockley, in Cardioskeletal Myopathies in Children and Young Adults, 2017. With the addition of substrate, the upstream redox centers (NAD+, ETFQOR, ETF) are reduced; and we propose it is this condition that results in a stabilized semireduced ETF and the maximum (but still low) rates from this system (Perevoshchikova et al., 2013). ETF and ETF:QO deficiencies are both inherited as autosomal recessive traits, and the genes encoding ETF:QO and the α- and β-subunits of ETF have been mapped to chromosome 4 (4q32>ter), 15 (15q23–25), and 19 (19q13.3), respectively. In these organisms, the etfAB genes are found next to an hdrF gene coding for a multidomain protein related to the HdrD, with a transmembrane, an FeS and two CCG domains (Grein et al., 2013; Strittmatter et al., 2009). Molecular analysis of 23 of our familial patients with RR-MADD has shown a robust prevalence of subjects with a variety of ETFDH mutations. Severe forms of GA II with congenital anomalies are more frequently associated with deficiency of ETF-QO. 2D ), likely because of the higher concentration of NADH within mitochondria ( 16 – 18 ). Jerry Vockley, in Emery and Rimoin's Principles and Practice of Medical Genetics, 2013. The protein monomer contains two different redox centres, i.e. InterPro. Another arrangement of the Etf module was found in the genomes of some SRP, including Desulfobacteraceae and Desulfobulbaceae families and Clostridia (Pereira et al., 2011). For riboflavin ETFDH mutations, resolution of symptoms occurs with riboflavin supplementation (up 150 mg daily). 14.8). Among patients with coenzyme Q10–deficient myopathy caused by ETFDH gene mutations, all showed improvement with coenzyme Q10 supplementation. Fractions with ratios between 6.5 and 10 should be pooled and further purified on a 20 μM ceramic hydroxyapatite column (Bio-Rad, Hercules, CA). By this pathway, energy from fat and amino acid oxidation can be used to generate protonmotive force and contribute to ATP synthesis. Patients with myopathic MADD may dramatically improve when treated with riboflavin. à FADH 2 produced in this reaction then donates 2 electrons to the mitochondrial ETC 2. Clinically, heterogeneity was exemplified by some patients presenting with a progressive extrapyramidal disorder with no organic aciduria. If variants of unknown significance are found, functional assays, including enzyme activity and acylcarnitine profiling, can be performed on fibroblasts. Interestingly, most ETFDH mutations in RR-MADD patients are located around the ubiquinone binding pocket.81,82 Since riboflavin is the precursor of FAD, it has been proposed that riboflavin responsiveness may result from the ability of FAD to act as a chemical chaperone that promotes folding of certain misfolded ETF:QO proteins, thereby ameliorating or normalizing disease symptoms.84, Stefano DiDonato, in Mitochondrial Disorders in Neurology, 1994. This frameshift mutation results in a protein that is not incorporated into mitochondria, but appears to be rapidly degraded [120]. Flavoprotein – reduced flavoprotein passes on 2H to co-enzyme Q. Coenzyme Q – similar in structure to Vitamin K Organic aciduria with excretion of hydroxyglutaric, ethylmalonic, and various dicarboxylic acids also is characteristic (14). Submitochondrial particles depleted of succinate dehydrogenase are still capable of ROS production ( 63 , 360 , 361 ), suggesting that the succinate dehydrogenase flavoprotein does not play an important role in ROS production. Between 200 and 250 g of pellet is processed at one time, and if frozen, are thawed overnight at 4°. Some patients may present with only late-onset myopathy [120]. For the riboflavin responsive-MAD deficiency, the challenge is to find the connection between variations in the ETFDH gene and the observed deficiency of a number of different mitochondrial dehydrogenases as well as deficiency of FAD and coenzyme Q10 (CoQ10).155 The isolated myopathic form of CoQ10 deficiency is caused by mutations in the ETF dehydrogenase gene and can be treated with CoQ10 and riboflavin.158, Franco Taroni, Cinzia Gellera, in Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Sixth Edition), 2020, The vast majority (>90%) of patients carry biallelic mutations in the ETFDH gene encoding ETF:QO.118,119,132 Most mutations seem to be private. Flavoproteins are involved in the electron transport chain and change their fluorescence according to … These and other studies [103,113] suggested that GA II with ETF deficiency was predominantly associated with mutations of the gene encoding α-ETF. If fractions are cloudy, they are centrifuged at 10,000 g for 30 min. The Intermediate Carriers in ETC are Nicotinamide adenine dinucleotide (NADH), Ubiquinone (CoQH2), Succinate Dehydrogenase, Cytochrome c, Cytochrome c oxidase. What the consequences might result from electron carriers in the ETC being bypassed? ETF is a soluble FAD-containing protein in the matrix that accepts electrons from nine primary flavoprotein dehydrogenases, including the four straight-chain-specific fatty acyl-CoA dehydrogenases (medium-, short-, long-, and very-long-chain dehydrogenases), as well as several dehydrogenases involved in the catabolism of amino acids (isovaleryl-CoA dehydrogenase, Ikeda & Tanaka, 1983b; glutaryl-CoA dehydrogenase, Lenich & Goodman, 1986; and short-branched-chain-CoA dehydrogenase, Ikeda & Tanaka, 1983a) and choline (sarcosine and dimethylglycine dehydrogenases, Frisell & Mackenzie, 1962). 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