Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales
Firstly, in this Doctoral Thesis, the synthesis and conformational analysis in aqueous solution of different alpha-methyl-alpha-amino acid diamides, derived from serine (Ser), threonine (Thr), beta-hydroxyciclobutane-alpha-amino acids and their corresponding model beta-O-glycopeptides, are reported....
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Universidad de La Rioja (España)
2009
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aminoácidos péptidos glicosilación glicopéptidos análisis conformacional dinámicas moleculares espectroscopía de Resonancia Magnética Nuclear amino acids peptides glycosylation glycopeptides conformation analysis molecular dynamics Nuclear Magnetic Resonance spectroscopy |
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aminoácidos péptidos glicosilación glicopéptidos análisis conformacional dinámicas moleculares espectroscopía de Resonancia Magnética Nuclear amino acids peptides glycosylation glycopeptides conformation analysis molecular dynamics Nuclear Magnetic Resonance spectroscopy Fernández Tejada, Alberto Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales |
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Firstly, in this Doctoral Thesis, the synthesis and conformational analysis in aqueous solution of different alpha-methyl-alpha-amino acid diamides, derived from serine (Ser), threonine (Thr), beta-hydroxyciclobutane-alpha-amino acids and their corresponding model beta-O-glycopeptides, are reported. From this study, it can be concluded that the incorporation of non-natural amino acids allows us to modulate as desired the conformational space of the model glycopeptides. The different conformations exhibited by these molecules could be a useful tool to obtain systems with conformational preferences "à la carte".
With the intention of expanding our novel small systems, we have synthesized larger glycopeptides similar to the previous ones. Their conformational analysis shows that the elongation of the backbone does not drastically affect the conformational preferences of these glycopeptides. Moreover, the synthesis of the first glycopeptide with a non natural amino acid at the underlying residue has been achieved. It is worth noting that the beta-O-glycosylation has a remarkable and completely different effect on the backbone of the peptides derived from natural and non-natural amino acids, respectively.
To go one step further, the synthesis of a glycopeptide incorporating the consensus sequence for O-glucose modification is reported. In addition, we have synthesized a novel glycopeptide and its corresponding peptide, in which the underlying serine residue has been replaced by the non-natural amino acid alpha-methylserine.
Finally, despite the importance of beta-O-GlcNAc glycosylation in fundamental biological processes, sparse structural information is known about beta-O-GlcNAc-Ser/Thr motifs. For this reason, we report the synthesis and conformational analysis of the simplest model glycopeptides derived from Ser and Thr glycosylated with beta-O-GlcNAc, as well as of the non-natural analogues incorporating alpha-methylserine and alfa-methylthreonine. The results demonstrate a distinct behavior of the glycosidic linkage (alternate conformations for the serine derivatives and eclipsed ones for the Thr-derived glycopeptides) allowing the carbohydrate moiety to adopt a completely different orientation. As a consequence, water pockets at key sites are responsible for modulating sugar-peptide interactions in these beta-O-GlcNAc glycopeptides. It is likely that these solvent pockets have important biological implications, providing the required presentation of the GlcNAc moieties to interact with their biological receptors. |
| author2 |
Peregrina García, Jesús Manuel (Universidad de La Rioja) |
| author_facet |
Peregrina García, Jesús Manuel (Universidad de La Rioja) Fernández Tejada, Alberto |
| format |
text (thesis) |
| author |
Fernández Tejada, Alberto |
| author_sort |
Fernández Tejada, Alberto |
| title |
Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales |
| title_short |
Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales |
| title_full |
Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales |
| title_fullStr |
Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales |
| title_full_unstemmed |
Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales |
| title_sort |
beta-o-glicosilación de péptidos que incorporan aminoácidos no naturales |
| publisher |
Universidad de La Rioja (España) |
| publishDate |
2009 |
| url |
https://dialnet.unirioja.es/servlet/oaites?codigo=18702 |
| work_keys_str_mv |
AT fernandeztejadaalberto betaoglicosilaciondepeptidosqueincorporanaminoacidosnonaturales |
| _version_ |
1718346587891040256 |
| spelling |
oai-TES00000013632019-05-14Beta-o-glicosilación de péptidos que incorporan aminoácidos no naturalesFernández Tejada, Albertoaminoácidospéptidosglicosilaciónglicopéptidosanálisis conformacionaldinámicas molecularesespectroscopía de Resonancia Magnética Nuclearamino acidspeptidesglycosylationglycopeptidesconformation analysismolecular dynamicsNuclear Magnetic Resonance spectroscopyFirstly, in this Doctoral Thesis, the synthesis and conformational analysis in aqueous solution of different alpha-methyl-alpha-amino acid diamides, derived from serine (Ser), threonine (Thr), beta-hydroxyciclobutane-alpha-amino acids and their corresponding model beta-O-glycopeptides, are reported. From this study, it can be concluded that the incorporation of non-natural amino acids allows us to modulate as desired the conformational space of the model glycopeptides. The different conformations exhibited by these molecules could be a useful tool to obtain systems with conformational preferences "à la carte". With the intention of expanding our novel small systems, we have synthesized larger glycopeptides similar to the previous ones. Their conformational analysis shows that the elongation of the backbone does not drastically affect the conformational preferences of these glycopeptides. Moreover, the synthesis of the first glycopeptide with a non natural amino acid at the underlying residue has been achieved. It is worth noting that the beta-O-glycosylation has a remarkable and completely different effect on the backbone of the peptides derived from natural and non-natural amino acids, respectively. To go one step further, the synthesis of a glycopeptide incorporating the consensus sequence for O-glucose modification is reported. In addition, we have synthesized a novel glycopeptide and its corresponding peptide, in which the underlying serine residue has been replaced by the non-natural amino acid alpha-methylserine. Finally, despite the importance of beta-O-GlcNAc glycosylation in fundamental biological processes, sparse structural information is known about beta-O-GlcNAc-Ser/Thr motifs. For this reason, we report the synthesis and conformational analysis of the simplest model glycopeptides derived from Ser and Thr glycosylated with beta-O-GlcNAc, as well as of the non-natural analogues incorporating alpha-methylserine and alfa-methylthreonine. The results demonstrate a distinct behavior of the glycosidic linkage (alternate conformations for the serine derivatives and eclipsed ones for the Thr-derived glycopeptides) allowing the carbohydrate moiety to adopt a completely different orientation. As a consequence, water pockets at key sites are responsible for modulating sugar-peptide interactions in these beta-O-GlcNAc glycopeptides. It is likely that these solvent pockets have important biological implications, providing the required presentation of the GlcNAc moieties to interact with their biological receptors.En esta Tesis Doctoral se aborda, en primer lugar, la síntesis y el estudio estructural en disolución acuosa de varias diamidas de alfa-metil-alfa-aminoácidos (péptidos modelo) derivados de Ser (serina), Thr (treonina) y beta-hidroxiciclobutan-alfa-aminoácidos, así como de sus correspondientes beta-O-glicopéptidos modelo. De este trabajo puede concluirse que, con la incorporación de aminoácidos no naturales, es posible modular a conveniencia el espacio conformacional de los glicopéptidos modelo, pudiendo obtenerse sistemas con preferencias conformacionales "a la carta". Con la intención de expandir estos novedosos sistemas pequeños, se han sintetizado glicopéptidos de mayor tamaño similares a los anteriores. Su análisis revela que el elongamiento de la cadena peptídica no afecta significativamente a las conformaciones observadas en los derivados más sencillos. Así, se ha realizado la síntesis del primer glicopéptido en el que el carbohidrato está directamente unido a un aminoácido no natural. Cabe destacar que el efecto de la beta-O-glicosilación sobre estos péptidos es importante y completamente distinto según incorporen aminoácidos naturales o no naturales. Dando un paso más, se ha sintetizado una secuencia glicopeptídica que aparece en biomoléculas de interés, donde el aminoácido Ser está glicosilado con beta-O-glucosa. Además, se ha sustituido esta Ser por su ánalogo cuaternario (alfa-metilserina) sintetizándose un nuevo glicopéptido no natural. Finalmente, dada la importancia biológica de la beta-O-glicosilación con GlcNAc -ya que está relacionada con la diabetes o el Alzheimer-, junto con la poca información estructural existente sobre ella, se ha llevado a cabo la síntesis y el análisis conformacional de los glicopéptidos modelo naturales de beta-O-GlcNAc (con Ser y Thr), así como de los no naturales que incorporan alfa-metilserina y alfa-metiltreonina. Los resultados revelan un comportamiento totalmente diferente del enlace glicosídico, con conformaciones alternadas para los derivados de serina y eclipsadas para los de treonina. Como consecuencia de esta diferencia existe una orientación relativa completamente distinta entre el resto carbohidrato y peptídico. Este hecho es responsable de la existencia de moléculas de agua puente en sitios clave que podrían tener importantes implicaciones biológicas, proporcionando el modo de presentación requerido del residuo de GlcNAc para interaccionar con sus receptores biológicos.Universidad de La Rioja (España)Peregrina García, Jesús Manuel (Universidad de La Rioja)Corzana López, Francisco (Universidad de La Rioja)2009text (thesis)application/pdfhttps://dialnet.unirioja.es/servlet/oaites?codigo=18702spaLICENCIA DE USO: Los documentos a texto completo incluidos en Dialnet son de acceso libre y propiedad de sus autores y/o editores. Por tanto, cualquier acto de reproducción, distribución, comunicación pública y/o transformación total o parcial requiere el consentimiento expreso y escrito de aquéllos. Cualquier enlace al texto completo de estos documentos deberá hacerse a través de la URL oficial de éstos en Dialnet. 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