000100670 001__ 100670
000100670 005__ 20210520140813.0
000100670 037__ $$aTESIS-2021-081
000100670 041__ $$aeng
000100670 080__ $$a577
000100670 1001_ $$aAnoz Carbonell, Ernesto
000100670 24500 $$aMolecular and dynamic mechanisms of prokaryotic and eukaryotic flavoenzymes: insights into their implication in human metabolism and health
000100670 260__ $$aZaragoza$$bUniversidad de Zaragoza, Prensas de la Universidad$$c2021
000100670 300__ $$a293
000100670 4900_ $$aTesis de la Universidad de Zaragoza$$v2021-81$$x2254-7606
000100670 500__ $$aPresentado: 22 01 2021
000100670 502__ $$aTesis-Univ. Zaragoza, , 2021$$bZaragoza, Universidad de Zaragoza$$c2021
000100670 506__ $$aby-nc-nd$$bCreative Commons$$c3.0$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es
000100670 520__ $$aLas 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. <br />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).<br />Esta Tesis Doctoral, presentada en la modalidad de compendio de publicaciones, incluye las siguientes publicaciones:<br />− Publicación I. Anoz-Carbonell E, Ribero M, Polo V, Velázquez-Campoy A, Medina M. 2020. Human riboflavin kinase: species-specific traits in the<br />biosynthesis of the FMN cofactor. The FASEB Journal, 34:10871–10886.<br />JCR Impact Factor 2019: 4.966. Rank: Q1 (57/297) Biochemistry and Molecular Biology; D1 (9/93) Biology; Q2 (58/195) Cell Biology.<br />− Publicación II. Leone P, Galluccio M, Quarta S, Anoz-Carbonell E, Medina M, Indiveri C, Barile M. 2019. Mutation of aspartate 238 in FAD<br />synthase isoform 6 increases the specific activity by weakening the FAD binding. International Journal of Molecular Sciences, 20(24):6203.<br />JCR Impact Factor 2019: 4.556. Rank: Q1 (74/297) Biochemistry and Molecular Biology; Q2 (48/177) Chemistry (multidisciplinary). <br />− Publicación III. Anoz-Carbonell E, Timson DJ, Pey AL, Medina M. 2020. The catalytic cycle of the antioxidant and cancer-associated human NQO1<br />enzyme: 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.<br />− 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.<br />− Publicación V. Lans I, Anoz-Carbonell E, Palacio-Rodríguez K, Aínsa JA, Medina M, Cossio P. 2020. In silico discovery and biological validation of<br />ligands 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.<br />
000100670 520__ $$aFlavoenzymes 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.<br />
000100670 521__ $$97073$$aPrograma de Doctorado en Bioquímica y Biología Molecular
000100670 6531_ $$aprocesos metabolicos
000100670 6531_ $$abioquimica molecular
000100670 6531_ $$aantibioticos
000100670 6531_ $$acoenzimas
000100670 700__ $$aMedina Trullenque, Milagros $$edir.
000100670 700__ $$aAínsa Claver, José Antonio$$edir.
000100670 7102_ $$aUniversidad de Zaragoza$$b
000100670 830__ $$9485
000100670 8560_ $$ftdr@unizar.es
000100670 8564_ $$s24139153$$uhttps://zaguan.unizar.es/record/100670/files/TESIS-2021-081.pdf$$zTexto completo (eng)
000100670 909CO $$ooai:zaguan.unizar.es:100670$$pdriver
000100670 909co $$ptesis
000100670 9102_ $$a$$b
000100670 980__ $$aTESIS