Molecular and dynamic mechanisms of prokaryotic and eukaryotic flavoenzymes: insights into their implication in human metabolism and health

Autor: Anoz Carbonell, Ernesto, Medina Trullenque, Milagros, Aínsa Claver, José Antonio
Rok vydání: 2021
Předmět:
Zdroj: Zaguán. Repositorio Digital de la Universidad de Zaragoza
instname
Zaguán: Repositorio Digital de la Universidad de Zaragoza
Universidad de Zaragoza
Popis: Las flavoenzimas y flavoproteínas son biomoléculas versátiles y diversas que están implicadas en el metabolismo energético y otros procesos celulares como la transducción de señales, la síntesis de nucleótidos, el plegamiento de proteínas o la defensa frente al estrés oxidativo. Estas proteínas tienen como cofactores los derivados de riboflavina (RF, vitamina B2), mononucleótido de flavina (FMN) y/o dinucleótido de flavina y adenina (FAD), que les confieren propiedades únicas y versátiles. Todos los organismos contienen flavoproteínas y flavoenzimas clave, y muchas de ellas se han convertido en interesantes dianas terapéuticas o herramientas biotecnológicas. En esta tesis, se ha indagado en los mecanismos moleculares de flavoenzimas y flavoproteínas con funciones metabólicas clave en procariotas y eucariotas, como las enzimas humanas RF quinasa (Publicación I), FAD sintetasa (FADS) (Publicación II) o NAD(P)H:quinona oxidorreductasa 1 (Publicación III), o las FADS procariotas (Publicaciones IV y V). La caracterización detallada de estas enzimas contribuye a la mejor comprensión de sus patologías asociadas, y sienta las bases de nuevas estrategias terapéuticas y del diseño de compuestos dirigidos a estas dianas. Por ejemplo, aquí presentamos una primera aproximación a la búsqueda de inhibidores de las FADS procariotas que puede contribuir a su explotación farmacológica como potencial agentes antimicrobianos (Publicaciones IV y V).Esta Tesis Doctoral, presentada en la modalidad de compendio de publicaciones, incluye las siguientes publicaciones:− Publicación I. Anoz-Carbonell E, Ribero M, Polo V, Velázquez-Campoy A, Medina M. 2020. Human riboflavin kinase: species-specific traits in thebiosynthesis of the FMN cofactor. The FASEB Journal, 34:10871–10886.JCR Impact Factor 2019: 4.966. Rank: Q1 (57/297) Biochemistry and Molecular Biology; D1 (9/93) Biology; Q2 (58/195) Cell Biology.− Publicación II. Leone P, Galluccio M, Quarta S, Anoz-Carbonell E, Medina M, Indiveri C, Barile M. 2019. Mutation of aspartate 238 in FADsynthase isoform 6 increases the specific activity by weakening the FAD binding. International Journal of Molecular Sciences, 20(24):6203.JCR Impact Factor 2019: 4.556. Rank: Q1 (74/297) Biochemistry and Molecular Biology; Q2 (48/177) Chemistry (multidisciplinary). − Publicación III. Anoz-Carbonell E, Timson DJ, Pey AL, Medina M. 2020. The catalytic cycle of the antioxidant and cancer-associated human NQO1enzyme: hydride transfer, conformational dynamics and functional cooperativity. Antioxidants, 9(9):E772. JCR Impact Factor 2019: 5.014. Rank: Q1 (56/297) Biochemistry and Molecular Biology; Q1 (7/61) Medicinal Chemistry; D1 (10/139) Food Science & Technology.− Publicación IV. 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. JCR Impact Factor 2018: 4.027. Rank: Q1 (10/61) Medicinal Chemistry; Q2 (84/299) Biochemistry and Molecular Biology.− Publicación V. Lans I, Anoz-Carbonell E, Palacio-Rodríguez K, Aínsa JA, Medina M, Cossio P. 2020. In silico discovery and biological validation ofligands FAD synthase, a promising new antimicrobial target. PLOS Computational Biology, 16(8):e1007898. JCR Impact Factor 2019: 4.700. Rank: Q1 (9/77) Biochemical Research Methods; Q1 (6/59) Mathematical & Computational Biology. 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.
Databáze: OpenAIRE
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