000016207 001__ 16207
000016207 005__ 20150325205538.0
000016207 037__ $$aTAZ-TFG-2014-1592
000016207 041__ $$aspa
000016207 1001_ $$aVizarraga Revuelto, David
000016207 24500 $$aIdentificación del sitio de unión de potenciales inhibidores de la FAD sintetasa para humanos mediante métodos de docking
000016207 260__ $$aZaragoza$$bUniversidad de Zaragoza$$c2014
000016207 506__ $$aby-nc-sa$$bCreative Commons$$c3.0$$uhttp://creativecommons.org/licenses/by-nc-sa/3.0/
000016207 520__ $$aThe FAD synthetase (FADs) from prokaryotes is a bifunctional protein that synthesizes FMN and FAD from riboflavin in two consecutive steps. FADs is folded in two modules, each associated with each one of its activities. However, in mammals FMN and FAD are synthesized by two independent proteins. Since FMN and FAD are required in all type of organisms to generate flavoenzymes and flavoproteins, which mediate many essential metabolic processes for maintenance of cell´s life, and the enzyme synthesizing FAD (FMN -adenililtransferasa activity, FMNAT) in mammals does not show sequence and structure conservation regarding to prokaryotic FADS, this activity in FADs has been recognized a potential target for the development of antimicrobials. At the moment, the best characterized prokaryotic FADs is that from Corynebacterium ammoniagenes, CaFADS. In this project we have used different computational methods to evaluate whether the knowledge adquired for CaFADS can be extrapolated to FADs inform human pathogens. We have chosen the enzyme from Streptococcus pneumoniae, SpFADs. Sequential and structural comparison between SpFADs and CaFADs shows very similar folds, with slight conformational changes in some loops that could contribute to the preference as substrate for reduced flavins in SpFADs. However, the substrates binding sites for the FMNAT activity conserve most residues involved in its stabilization, as well as amino acids at the active site are either conserved or show conservative substitutions. The interaction with substrates in the FMNAT site was studied in detail by docking simulations with ATP, FMNred, FMNox, FADred and FADox. In general, these are located at equivalent positions as described in models of CaFADS. However, SpFADs is able to accommodate FMNred, but not FMNox, while the result is less clearly for FAD. A hydrogen bond stabilizes the interaction between the N5 of flavin and the A103 in the reduced state, but not in its oxidized state, It might be responsible for the preference for the reduced form. Finally, we have also employed docking simulations to predict whether a series of compounds in vitro identified sas inhibitors of the FMNAT activity of FAD CaFADS, are also able to bind at FMNAT site of the SpFADs. The obtained results, indicate that it is worthy to experimentally test these compounds as potential inhibitors of SpFADs.
000016207 521__ $$aGraduado en Biotecnología
000016207 540__ $$aDerechos regulados por licencia Creative Commons
000016207 700__ $$aMedina Trullenque, María Milagros$$edir.
000016207 700__ $$aSebastián Valverde, María$$edir.
000016207 7102_ $$aUniversidad de Zaragoza$$bBioquímica y Biología Molecular y Celular$$cBioquímica y Biología Molecular
000016207 8560_ $$f627547@celes.unizar.es
000016207 8564_ $$s314380$$uhttps://zaguan.unizar.es/record/16207/files/TAZ-TFG-2014-1592_ANE.pdf$$yAnexos (spa)
000016207 8564_ $$s8015965$$uhttps://zaguan.unizar.es/record/16207/files/TAZ-TFG-2014-1592.pdf$$yMemoria (spa)
000016207 909CO $$ooai:zaguan.unizar.es:16207$$pdriver$$ptrabajos-fin-grado
000016207 950__ $$a
000016207 980__ $$aTAZ$$bTFG$$cCIEN