Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina
In the last two decades, the glycobiology field, which comprises the study of carbohydrates, glycopeptides and glycoproteins, has attracted considerable attention due to these molecules are involved in many fundamental processes of the life. One of these processes is known as molecular recognition o...
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Universidad de La Rioja (España)
2014
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In the last two decades, the glycobiology field, which comprises the study of
carbohydrates, glycopeptides and glycoproteins, has attracted considerable
attention due to these molecules are involved in many fundamental
processes of the life. One of these processes is known as molecular
recognition of ligands by receptors. In particular, this interaction is tightly
related to the 3D structure they adopt.
In this context, this Thesis focuses on searching new non?natural
glycosylamino acids that display different conformations from those that
adopt glycosylated natural amino acids. In this sense, several glycosylamino
acids have been synthesized, which incorporate ?,??disubstituted amino
acids. The structural preferences of these new compounds were elucidated,
combining NMR experiments and Molecular Dynamics simulations. As a
result, the synthetic modifications made in the amino acid moiety can be
regarded as a tool to develop glycosylated derivatives with conformations a
la cartè.
Another issue which this Thesis focuses on, is to find out why glucose only
appear linked to serine, when it is incorporated in a certain peptide sequence
(consensus sequence). In particular, in this work, we studied the consensus
sequence for ??O?glycosylation with glucose. For this purpose, two peptides
and one glycopeptide were synthesized. As a first approaching, we calculated
the spatial distribution of the hydroxyl group of serine, that later will be
glycosylated, and interestingly it is exposed to the solvent, therefore the
glycosylation would be easier.
On the other hand, this Thesis tries to shed some light to the controversial
about the role that peptide moiety plays in the molecular recognition of
glycopeptides by lectins. In this regard, two glycine rich glycopeptides were
synthesized, Gly?Gly?Xxx?Gly?Gly, where Xxx was replaced by Thr/Ser(??OGalNac).
Besides, conformational studies both in the free and bound?states were developed. In addition, thermodynamic parameters corresponding to
molecular recognition of each glycopeptides by two specific lectins were
obtained by microcalorimetry. All this work shows the importance of the
amino acid linked to the carbohydrate plays in the molecular recognition
process. In fact, it is not a mere spectator but it develops a role as modulator
agent. |
| author2 |
Peregrina García, Jesús Manuel (Universidad de La Rioja) |
| author_facet |
Peregrina García, Jesús Manuel (Universidad de La Rioja) Somovilla Busto, Víctor Jesús |
| format |
text (thesis) |
| author |
Somovilla Busto, Víctor Jesús |
| spellingShingle |
Somovilla Busto, Víctor Jesús Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina |
| author_sort |
Somovilla Busto, Víctor Jesús |
| title |
Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina |
| title_short |
Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina |
| title_full |
Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina |
| title_fullStr |
Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina |
| title_full_unstemmed |
Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosamina |
| title_sort |
síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-n-acetilgalactosamina |
| publisher |
Universidad de La Rioja (España) |
| publishDate |
2014 |
| url |
https://dialnet.unirioja.es/servlet/oaites?codigo=44163 |
| work_keys_str_mv |
AT somovillabustovictorjesus sintesisyanalisisconformacionaldeglicopeptidosqueincorporanßglucosayanacetilgalactosamina |
| _version_ |
1718346622025334784 |
| spelling |
oai-TES00000072572019-07-04Síntesis y análisis conformacional de glicopéptidos que incorporan ß-glucosa y a-N-acetilgalactosaminaSomovilla Busto, Víctor JesúsIn the last two decades, the glycobiology field, which comprises the study of carbohydrates, glycopeptides and glycoproteins, has attracted considerable attention due to these molecules are involved in many fundamental processes of the life. One of these processes is known as molecular recognition of ligands by receptors. In particular, this interaction is tightly related to the 3D structure they adopt. In this context, this Thesis focuses on searching new non?natural glycosylamino acids that display different conformations from those that adopt glycosylated natural amino acids. In this sense, several glycosylamino acids have been synthesized, which incorporate ?,??disubstituted amino acids. The structural preferences of these new compounds were elucidated, combining NMR experiments and Molecular Dynamics simulations. As a result, the synthetic modifications made in the amino acid moiety can be regarded as a tool to develop glycosylated derivatives with conformations a la cartè. Another issue which this Thesis focuses on, is to find out why glucose only appear linked to serine, when it is incorporated in a certain peptide sequence (consensus sequence). In particular, in this work, we studied the consensus sequence for ??O?glycosylation with glucose. For this purpose, two peptides and one glycopeptide were synthesized. As a first approaching, we calculated the spatial distribution of the hydroxyl group of serine, that later will be glycosylated, and interestingly it is exposed to the solvent, therefore the glycosylation would be easier. On the other hand, this Thesis tries to shed some light to the controversial about the role that peptide moiety plays in the molecular recognition of glycopeptides by lectins. In this regard, two glycine rich glycopeptides were synthesized, Gly?Gly?Xxx?Gly?Gly, where Xxx was replaced by Thr/Ser(??OGalNac). Besides, conformational studies both in the free and bound?states were developed. In addition, thermodynamic parameters corresponding to molecular recognition of each glycopeptides by two specific lectins were obtained by microcalorimetry. All this work shows the importance of the amino acid linked to the carbohydrate plays in the molecular recognition process. In fact, it is not a mere spectator but it develops a role as modulator agent.El campo de la glicobiología, es decir, el estudio de carbohidratos, glicopéptidos y glicoproteínas, ha experimentado un gran auge en las últimas dos décadas debido a la multitud de procesos fundamentales en los que se ven inmersos este tipo de moléculas. Uno de estos procesos es el reconocimiento molecular de un determinado ligando (carbohidrato, péptido o glicopéptido) por parte de un receptor (proteína). Además, es bien sabido que esta interacción está íntimamente ligada con la estructura tridimensional tanto del receptor como del ligando. Por todo ello, la presente tesis doctoral busca en primer lugar, disponer de nuevos glicosilaminoácidos no naturales que muestran conformaciones distintas a las exploradas por sus análogos naturales. Para ello, se recurre a la síntesis de derivados que incorporan aminoácidos de diseño, en concreto, aminoácidos ?,?? disustituidos. Una vez conocidas las preferencias estructurales de estos nuevos residuos, se pueden desarrollar derivados glicosilados con conformaciones a la carta. Otro aspecto que se estudia en la presente Tesis Doctoral es averiguar por qué la glucosa se encuentra unida a Ser cuando ésta se encuentra flanqueada por una determinada secuencia peptídica (secuencia de consenso). En concreto, se ha estudiado la secuencia que con frecuencia incorpora la ??O?glucosilación. Con este objetivo, se han sintetizado dos péptidos y un glicopéptido, y como una primera aproximación se muestra que la disposición del grupo hidroxilo que después va a ser glicosilado se encuentra expuesto hacia el disolvente de tal manera que facilitaría la unión del carbohidrato. Por otra lado, otra parte del trabajo, arroja algo de luz a la controversia que existe acerca del papel que la parte peptídica juega en el reconocimiento deglicopéptidos por lectinas. En este sentido, se han sintetizado dos glicopéptidos ricos en glicinas, Gly?Gly?Xxx?Gly?Gly, donde Xxx puede ser Thr/Ser(??O?GalNac). Además, se ha llevado a cabo el estudio conformacional de ambos, en el estado libre y en el estado asociado y se han determinado experimentalmente los valores termodinámicos de la interacción de cada una de las lectinas con ambos glicopéptidos, a través de microcalorimetrías. En esta parte de la Tesis se deja claro que el aminoácido al que está unido la ??N?acetilgalactosmina no es un mero espectador en el proceso de reconocimiento molecular de dicho carbohidrato por parte de la lectina (proteína), sino que presenta un claro papel como agente modulador.Universidad de La Rioja (España)Peregrina García, Jesús Manuel (Universidad de La Rioja)Corzana López, Francisco (Universidad de La Rioja)2014text (thesis)application/pdfhttps://dialnet.unirioja.es/servlet/oaites?codigo=44163spaLICENCIA 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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