Resumen de Molecular and dynamic mechanisms of prokaryotic and eukaryotic flavoenzymes: insights into their implication in human metabolism and health
Flavoenzymes and flavoproteins are versatile and diverse biomolecules that are implicated in the energetic metabolism and other cellular processes such as signalling, nucleotide synthesis, protein folding or defense against oxidative stress. These proteins have as cofactors the riboflavin (RF, vitamin B2) derivatives flavin mononucleotide (FMN) and/or flavin adenine dinucleotide (FAD), which confer them their unique and versatile properties. All organisms contain key flavoproteins and flavoenzymes, and many of them are becoming interesting as therapeutic targets or biotechnological tools.
In the present thesis, we have delved into the molecular mechanisms of flavoenzymes with key metabolic functions in prokaryotes and eukaryotes, such as the human RF kinase (Publication I) and FAD synthase (FADS) (Publication II), human NAD(P)H:quinone oxidoreductase 1 (Publication III), and prokaryotic FADS (Publications IV and V). The detailed characterization of these enzymes contributes to the better understanding of their associated pathologies, and provides a framework to novel therapeutic strategies and to the design of compounds targeting them. For instance, here we show a first approximation for identification of inhibitors of the prokaryotic FADS that might contribute to exploit them as pharmacological antimicrobial drugs (Publications IV and V).
This Doctoral Thesis, presented in the form of a compendium of publications, comprises the following publications:
− Anoz-Carbonell E, Ribero M, Polo V, Velázquez-Campoy A, Medina M. 2020. Human riboflavin kinase: species-specific traits in the biosynthesis of the FMN cofactor. The FASEB Journal, 34:10871–10886.
− Leone P, Galluccio M, Quarta S, Anoz-Carbonell E, Medina M, Indiveri C, Barile M. 2019. Mutation of aspartate 238 in FAD synthase isoform 6 increases the specific activity by weakening the FAD binding. International Journal of Molecular Sciences, 20(24):6203.
− Anoz-Carbonell E, Timson DJ, Pey AL, Medina M. 2020. The catalytic cycle of the antioxidant and cancer-associated human NQO1 enzyme: hydride transfer, conformational dynamics and functional cooperativity. Antioxidants, 9(9):E772.
− Sebastián M, Anoz-Carbonell E, Gracia B, Cossio P, Aínsa JA, Lans I, Medina M. 2018. Discovery of antimicrobial compounds targeting bacterial type FAD synthetases. Journal of Enzyme Inhibition and Medicinal Chemistry, 33:1, 241-254.
− Lans I, Anoz-Carbonell E, Palacio-Rodríguez K, Aínsa JA, Medina M, Cossio P. 2020. In silico discovery and biological validation of ligands FAD synthase, a promising new antimicrobial target. PLOS Computational Biology, 16(8):e1007898.
