Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations

Programa de Doctorat de Biotecnologia

Detalhes bibliográficos
Autor: Iglesias Fernández, Javier
Tipo de documento: tese
Estado:Versão publicada
Data de publicação:2014
País:España
Recursos:CBUC, CESCA
Repositório:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/283551
Acesso em linha:http://hdl.handle.net/10803/283551
Access Level:Acceso aberto
Palavra-chave:Glúcids
Glúcidos
Glucides
Catàlisi
Catálisis
Catalysis
Dinàmica molecular
Dinámica molecular
Molecular dynamics
Enzims
Enzimas
Enzymes
Ciències de la Salut
577
id ES_3e43ebfb40e332a2efbe4ecc082d361c
oai_identifier_str oai:www.tdx.cat:10803/283551
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
title Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
spellingShingle Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
Iglesias Fernández, Javier
Glúcids
Glúcidos
Glucides
Catàlisi
Catálisis
Catalysis
Dinàmica molecular
Dinámica molecular
Molecular dynamics
Enzims
Enzimas
Enzymes
Ciències de la Salut
577
title_short Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
title_full Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
title_fullStr Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
title_full_unstemmed Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
title_sort Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulations
dc.creator.none.fl_str_mv Iglesias Fernández, Javier
author Iglesias Fernández, Javier
author_facet Iglesias Fernández, Javier
author_role author
dc.contributor.none.fl_str_mv Rovira i Virgili, Carme
Badia Palacín, Josefa
Universitat de Barcelona. Facultat de Farmàcia
dc.subject.none.fl_str_mv Glúcids
Glúcidos
Glucides
Catàlisi
Catálisis
Catalysis
Dinàmica molecular
Dinámica molecular
Molecular dynamics
Enzims
Enzimas
Enzymes
Ciències de la Salut
577
topic Glúcids
Glúcidos
Glucides
Catàlisi
Catálisis
Catalysis
Dinàmica molecular
Dinámica molecular
Molecular dynamics
Enzims
Enzimas
Enzymes
Ciències de la Salut
577
description Programa de Doctorat de Biotecnologia
publishDate 2014
dc.date.none.fl_str_mv 2014
2014
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/283551
url http://hdl.handle.net/10803/283551
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 167 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406521680461824
spelling Elucidating catalytic mechanisms of glycoside hydrolases and transferases by means of ab initio molecular dynamics simulationsIglesias Fernández, JavierGlúcidsGlúcidosGlucidesCatàlisiCatálisisCatalysisDinàmica molecularDinámica molecularMolecular dynamicsEnzimsEnzimasEnzymesCiències de la Salut577Programa de Doctorat de BiotecnologiaCarbohydrates play a central role in transport and storage of energy and as molecular building blocks. Additionally, glycoconjugates, specifically glycoproteins and glycolipids, are important components of cell surfaces and the extracellular environment that mediate cellular and molecular interactions. Defects in glycosylation are associated with human diseases while the ability of glycans to modulate immune responses leads to them playing a critical role in susceptibility and resistance to pathogens. This huge amount of glycan structures requires the existence of a diverse group of degrading and remodelling enzymes: glycoside hydrolases (GHs) and glycoside transferases (GTs). GHs and GTs are highly specific enzymes responsible of the hydrolysis (GHs) and formation (GTs) of glycosidic bonds in carbohydrates. They are responsible for the modification of polysaccharides and glycoconjugates involved in numerous biological processes such as pathogenesis mechanisms, cell-cell recognition and polysaccharide degradation for biofuel processing. Knowledge of their enzymatic mechanism at a molecular level is crucial to understand how carbohydrates are assembled/degraded in organisms, as well as in developing new drugs. The detailed characterization of the transition state of the chemical reaction in which they participate, for instance, is key for the development of TS-analog inhibitors, which are known to be very efficient. In recent years, our group has investigated the implications of the conformational changes on the substrate during catalysis in several GHs and has related these changes with the conformations that can be sampled by a single sugar unit (e.g. glucose). This was analyzed by adapting sugar puckering coordinates as collective variables in ab initio metadynamics simulations. These studies are having a significant impact not only in the theoretical community but also in biochemistry and biophysics, because of the possibility to predict substrate catalytic itineraries for GHs. In this thesis, we extend these analyses to other sugar molecules to verify the proposed catalytic itineraries and also to GH inhibitors and sugar oxocarbenium ions to gain insights into transition state mimicry. Unlike GHs, known to operate by means of a double displacement mechanism, the reaction mechanism of retaining GTs is controversial. Both a two-step mechanism (by analogy to retaining glycoside hydrolases) and a one-step mechanism have been proposed and studied by means of quantum mechanics / molecular mechanics (QM/MM) simulations. Here, we applied this methodology to elucidate the catalytic mechanism of an engineered glycoside hydrolase and a glycoside transferase, giving support for a front-face single displacement mechanism.Los azúcares presentan una gran variabilidad estructural que es aprovechada por los diferentes organismos para realizar una multitud de procesos biológicos, que incluyen el almacenamiento de energía, el reconocimiento y la señalización celular. Las glicosil hidrolasas y glicosil transferasas son las enzimas responsables de la hidrólisis y síntesis, respectivamente, de estos biopolímeros y por lo tanto están presentes en una gran variedad de procesos celulares. Las técnicas de modelado molecular permiten analizar estos procesos biológicos, como por ejemplo la reacción de formación de un enlace entre azúcares, a un nivel atomístico. De esta forma, se pueden describir los cambios conformacionales que se producen en el sustrato al unirse a la enzima, identificar el estado de transición de la reacción química y determinar otros aspectos fundamentales de la catálisis enzimática.Universitat de BarcelonaRovira i Virgili, CarmeBadia Palacín, JosefaUniversitat de Barcelona. Facultat de Farmàcia201420152014info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion167 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/283551TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/2835512026-06-14T12:46:07Z
score 15.300724

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