Dokument: Stochastic modelling of glycogen: structure, metabolism, and related disorders
| Titel: | Stochastic modelling of glycogen: structure, metabolism, and related disorders | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65762 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240711-144039-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Rousset, Yvan [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Ebenhöh, Oliver [Gutachter] Prof. Lercher, Martin [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Organisms must efficiently manage their energy resources to survive as nutrient availability can vary significantly over time, and other stresses may temporarily increase energy demands. Therefore, internal energy stores are necessary to respond to changes in energy supply and demand. These stores are filled when nutrients are abundant and depleted when demand exceeds available supply. Glucose plays a central role in energy metabolism for most organisms, as it serves as a direct substrate for catabolic pathways. Animals, fungi, and most bacteria store glucose as glycogen, a macro-polymer made of glucose organized in branched linear chains. Cycles of glycogen degradation and breakdown ensure maintaining glucose homeostasis, as well as fueling other organs in mammals. Four enzymes are directly responsible for glycogen synthesis and degradation: glycogen synthase, glycogen branching enzyme, glycogen phosphorylase, and glycogen debranching enzyme. The interplay between these four enzymes ensures the correct building of the glycogen molecule. Despite being widely investigated since 1950, numerous questions remain unclear. The interplay between the kinetics of these enzymes and the structure of
glycogen is not fully characterized. The precise mechanism at work during branching and debranching is not well understood. Moreover, the effects of certain genetic conditions on glycogen metabolism and structure is still to be explored. In the first part, I introduce a spatially resolved and stochastic model for the synthesis and degradation of glycogen. By using the Gillespie algorithm to track single reaction events, the model allows for a detailed exploration of glycogen structure. Experimental measurements of structural features as signatures of enzyme activities were used to constrain different branching scenarios. The model can also replicate numerous other experimental data, such as the density profile and radius of the glycogen granules. Additionally, the model can be used to investigate other effects such as steric hindrance and enzymatic mechanisms, potentially in polysaccharides other than glycogen. In the second part of this work, I developed algorithmic methods to couple deterministic chemical systems with stochastic ones. I present the periodic-coupling algorithm, which comprises a stochastic module communicating with a classical ordinary differential equation (ODE) solver at a given frequency, enabling the tracking of single stochastic reactions in a regular ODE model. The algorithm outperforms a full stochastic approach and enables the coupling of our 3D structural model to a kinetic model of glycogen metabolism. With this approach, one can simultaneously track the evolution of a small glycogen metabolic model and the glycogen granule properties, which allows for a characterization of the reciprocal effect of the granule structure on the kinetic model. Additionally, I investigated simplified models for glycogen storage diseases that I discuss. Notably, this approach is able to grasp the effect of the debranching reaction on glucose homeostasis. Finally, I provide a discussion on the fractal view of glycogen, as well as a toy model to establish the basics of further investigation of 𝜷 and 𝜶 glycogen granule interactions. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 11.07.2024 | |||||||
| Dateien geändert am: | 11.07.2024 | |||||||
| Promotionsantrag am: | 20.04.2023 | |||||||
| Datum der Promotion: | 31.08.2023 |
