Glycolysis: thermodynamics and pathway predictions

热力学与已发表的模型的应用仍然不能令人满意地预测生化途径的可行性。这是因为到目前为止基本数据要么没有在文献中公布，要么现有数据非常不准确(基团贡献法)。这些基本数据包括纯代谢物的热力学数据以及反应平衡数据。后者取决于许多参数(例如，pH、温度、细胞质中反应介质的组成)。这些数据被包含在严格的模型中，这些模型从数学上描述了代谢途径。为了使这些模型更具预测性，必须提供关于纯代谢物和反应平衡的准确热力学数据。此外，必须考虑分子拥挤等影响，以使代谢网络更好地预测。如果有这样的数据，它们将适用于描述代谢网络的数学模型，类似于已经达到的类似复杂性的系统(例如，炼油厂)。本项目旨在使用新的热力学工具来定量确定纯代谢物的性质和反应平衡，以便预测代谢途径的热力学。糖酵解是为了这个目的而选择的，因为特别是糖酵解的热力学还不清楚。在这项建议中，体外研究被建议解决生命系统中典型的复杂相互作用(盐和分子聚集物的存在)。这将允许调查它们对代谢反应热力学的影响，这是一个在社会上受到强烈讨论的问题。在第一步，将确定选定代谢物和糖酵解中个别反应的新的基本数据。细胞质中的真实条件对这些数据的影响将被调查，例如，细胞质的pH值或组成。在第二步中，将检验生物典型现象(物种多样性、拥挤)对热力学和质量流计算的影响。这将最终展示一致的热力学数据如何提高代谢网络计算的预测能力。为了实现这一目标，热化学、量子化学和热力学必须与物质流分析相结合：-Verevkin：确定和预测纯代谢物的基本数据-Hold：确定和预测单个反应步骤的反应平衡，并在真实细胞条件的影响下-Maskow：在非平衡条件下的简化和真实代谢网络中应用这些数据所获得的项目结果将应用于生物技术(生物工程、系统生物学)。

The application of thermodynamics with published models still does not allow satisfactory predictions of the feasibility of biochemical pathways. This is due to the fact that basic data are either not published in the literature so far or available data is very inaccurate (group contribution methods). These basic data include thermodynamic data for pure metabolites as well as data on reaction equilibria. The latter depend on a number of parameters (e.g., pH, temperature, composition of the reaction medium in the cytoplasm). These data are included in rigorous models that depict metabolic pathways mathematically. To make these models more predictive, accurate thermodynamic data on pure metabolites as well as on reaction equilibria must be available. Further, effects like molecular crowding must be considered to make metabolic networks better predictable. If such data were available, they would be applicable in mathematical models for the description of metabolic networks, similar to it what has already been reached for systems of comparable complexity (e.g., petroleum refineries).This project aims to use new thermodynamic tools for the quantitative determination of properties of pure metabolites and reaction equilibria in order to predict the thermodynamics of the metabolic pathways. Glycolysis is chosen for that purpose as especially thermodynamics of glycolysis is still not understood. In this proposal, in vitro studies are suggested that address complex interactions that are typical for living systems (presence of salts and molecular crowders). This will allow investigating their influence on the thermodynamics of metabolic reactions, a question that is strongly discussed in the community.In a first step, new basic data for selected metabolites and individual reactions within glycolysis will be determined. The influence of real conditions in the cytoplasm on these data will be investigated e.g., pH or composition of the cytoplasm. In a second step, the effects of bio-typical phenomena (species diversity, crowding) on thermodynamics and mass-flow calculations will be examined. This will finally show how consistent thermodynamic data can improve the predictive power of metabolic network calculations.To achieve the goal, thermochemistry, quantum chemistry and thermodynamics have to be combined with material flow analysis:- Verevkin: Determination and prediction of basic data of the pure metabolites- Held: Determination and prediction of the reaction equilibria of the individual reaction steps and under the influence of real cell conditions- Maskow: application of these data in simplified and real metabolic networks under non-equilibrium conditionsThe project results obtained will be applied in biotechnology (bioengineering, systems biology).