Henriques 2021 Gene
| Henriques BJ, Katrine Jentoft Olsen R, Gomes CM, Bross P (2021) Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease. Gene 776:145407. https://doi.org/10.1016/j.gene.2021.145407 |
Henriques BJ, Katrine Jentoft Olsen R, Gomes CM, Bross P (2021) Gene
Abstract: Electron transfer flavoprotein (ETF) is an enzyme with orthologs from bacteria to humans. Human ETF is nuclear encoded by two separate genes, ETFA and ETFB, respectively. After translation, the two subunits are imported to the mitochondrial matrix space and assemble into a heterodimer containing one FAD and one AMP as cofactors. ETF functions as a hub taking up electrons from at least 14 flavoenzymes, feeding them into the respiratory chain. This represents a major source of reducing power for the electron transport chain from fatty acid oxidation and amino acid degradation. Transfer of electrons from the donor enzymes to ETF occurs by direct transfer between the enzyme bound flavins, a process that is tightly regulated by the polypeptide chain and by protein:protein interactions. ETF, in turn relays electrons to the iron sulfur cluster of the inner membrane protein ETF:QO, from where they travel via the FAD in ETF:QO to ubiquinone, entering the respiratory chain at the level of complex III. ETF recognizes its dehydrogenase partners via a recognition loop that anchors the protein on its partner followed by dynamic movements of the ETF flavin domain that bring redox cofactors in close proximity, thus promoting electron transfer. Genetic mutations in the ETFA or ETFB genes cause the Mendelian disorder multiple acyl-CoA dehydrogenase deficiency (MADD; OMIM #231680). We here review the knowledge on human ETF and investigations of the effects of disease-associated missense mutations in this protein that have promoted the understanding of the essential role that ETF plays in cellular metabolism and human disease.
• Bioblast editor: Gnaiger E
Selected quotations
- ETF .. was first described in 1954, and named dye/cyt reducing factor (Crane and Beinert, 1954). In 1956 its name was changed to electron-transferring flavoprotein, acronym ETF (Crane and Beinert, 1956), ..
- Two decades later, the Beinert lab again discovered the enzyme that links ETF to the respiratory chain: Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO; gene name ETFDH) (Ruzicka and Beinert, 1977).
- Human ETF receives electrons from at least 14 FAD-linked dehydrogenation reactions and hands them over to electron transfer flavoprotein-ubiquinone oxidoreductase (ETF:QO), which in turn transfers them to Coenzyme Q10 (CoQ10) in the inner mitochondrial membrane (Fig. 1; Table 1). This feeds the CoQ10 pool of the electron transport chain (ETC), similarly to complexes I and II.
- ETF is a hub in mitochondrial redox metabolism. Amino acid catabolism, fatty acid oxidation, and choline metabolism are among the metabolic routes in mitochondria in which ETF intervenes as an electron acceptor, oxidizing multiple other flavoproteins.
- One group of enzymes transferring electrons to ETF are acyl-CoA dehydrogenases (ACDHs) involved in β-oxidation of straight-chain fatty acids (VLCAD, LCAD, MCAD, and SCAD) and three other ACDHs (ACAD9, ACAD10, and ACAD11) that dehydrogenate acyl-chain substrates.
- ACAD10 and ACAD11 have been shown to dehydrogenate certain particularly long-chain and branched-chain acyl-CoA’s.
- A second group consists of ACDHs handling intermediates in the degradation of amino acids.
- A third group is composed of dehydrogenases involved in choline metabolism.
- The involvement in a multiplicity of metabolic processes in the mitochondrial matrix indicates that ETF and ETF:QO represent a regulatory hub that controls the electron flow to the respiratory chain from a series of flavoenzymes.
- Another important characteristic is the ETF greenish fluorescence, with an emission peak around 490 nm.
- .. to improve electron flow within the different pathways it has been suggested that ETF is present in some specific functional assemblies, composed of dehydrogenases from mitochondrial fatty acid β-oxidation, ETF:QO, CoQ10 and complex III (Parker and Engel, 2000).
- further evidence for the formation of a respiratory super-complex composed of multiple ACDHs, ETF, ETF: QO, and trifunctional protein (Wang et al., 2019).
- ETF is a two-electron and two-proton transporter as its FAD undergoes successive reduction via two-consecutive one-electron transfer steps, with the formation of an intermediate one-electron red flavin semiquinone species (FAD•−), which is then fully reduced to FADH2 with the uptake of one additional electron and two protons (Fig. 4a).
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Preparation: Enzyme
Pathway: F
