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Open AccessArticle

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

Laboratory of Biochemistry; Molecular and Structural Biology; Department of Biosciences, Biotechnologies, Biopharmaceutics; University of Bari; Via E. Orabona 4; 70125 Bari, Italy
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Authors to whom correspondence should be addressed.
These authors declared the equally contribution.
J. Clin. Med. 2019, 8(12), 2117; https://doi.org/10.3390/jcm8122117
Received: 11 October 2019 / Revised: 11 November 2019 / Accepted: 18 November 2019 / Published: 2 December 2019
(This article belongs to the Special Issue The Rise of Mitochondria in Medicine)
Flavoprotein oxidoreductases are members of a large protein family of specialized dehydrogenases, which include type II NADH dehydrogenase, pyridine nucleotide-disulphide oxidoreductases, ferredoxin-NAD+ reductases, NADH oxidases, and NADH peroxidases, playing a crucial role in the metabolism of several prokaryotes and eukaryotes. Although several studies have been performed on single members or protein subgroups of flavoprotein oxidoreductases, a comprehensive analysis on structure–function relationships among the different members and subgroups of this great dehydrogenase family is still missing. Here, we present a structural comparative analysis showing that the investigated flavoprotein oxidoreductases have a highly similar overall structure, although the investigated dehydrogenases are quite different in functional annotations and global amino acid composition. The different functional annotation is ascribed to their participation in species-specific metabolic pathways based on the same biochemical reaction, i.e., the oxidation of specific cofactors, like NADH and FADH2. Notably, the performed comparative analysis sheds light on conserved sequence features that reflect very similar oxidation mechanisms, conserved among flavoprotein oxidoreductases belonging to phylogenetically distant species, as the bacterial type II NADH dehydrogenases and the mammalian apoptosis-inducing factor protein, until now retained as unique protein entities in Bacteria/Fungi or Animals, respectively. Furthermore, the presented computational analyses will allow consideration of FAD/NADH oxidoreductases as a possible target of new small molecules to be used as modulators of mitochondrial respiration for patients affected by rare diseases or cancer showing mitochondrial dysfunction, or antibiotics for treating bacterial/fungal/protista infections.
Keywords: flavoprotein oxidoreductases; apoptosis-inducing factor (AIF); type II NADH dehydrogenase (NDH-2); thioredoxin reductase (TrxR1); dihydrolipoamide dehydrogenase (DLD); ubiquinone; molecular modeling; protein shape; antibiotics; mitochondrial respiration flavoprotein oxidoreductases; apoptosis-inducing factor (AIF); type II NADH dehydrogenase (NDH-2); thioredoxin reductase (TrxR1); dihydrolipoamide dehydrogenase (DLD); ubiquinone; molecular modeling; protein shape; antibiotics; mitochondrial respiration
MDPI and ACS Style

Trisolini, L.; Gambacorta, N.; Gorgoglione, R.; Montaruli, M.; Laera, L.; Colella, F.; Volpicella, M.; De Grassi, A.; Pierri, C.L. FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function. J. Clin. Med. 2019, 8, 2117.

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