Biology subjects

Hishida, A.

Publications and source records attributed to Hishida, A..

3 recordsLinked to original sources

bioRxiv2025

Analysis of Metabolic Stability under Environmental Perturbations Using a Kinetic Model

Cells robustly maintain metabolic function despite environmental fluctuations affecting reaction kinetics, yet kinetic models often exhibit fragility. We investigated this discrepancy by examining the effects of temperature changes on a kinetic model of Escherichia coli central metabolism. A gradual temperature decrease caused an abrupt transition to a state with sharply reduced ATP production efficiency, triggered by an elevated ATP/ADP ratio creating a glycolysis bottleneck. Introducing a rapid ATP-ADP exchange reaction prevented this ATP/ADP ratio surge and sustained high ATP production efficiency across temperatures. Furthermore, altering enzyme abundances similarly maintained high ATP production, with predicted enzyme regulation aligning with experimental observations in E. coli at low temperatures. Our findings indicate that balancing key cofactors, such as the ATP/ADP ratio, is crucial for preserving metabolic stability under environmental perturbations.

systems biology↗

bioRxiv2023

Patterns of change in regulatory modules of chemical reaction systems induced by network modification

Cellular functions are realized through the dynamics of chemical reaction networks formed by thousands of chemical reactions. Numerical studies have empirically demonstrated that small differences in network structures among species or tissues can cause substantial changes in dynamics. However, the existence of a general principle for behavior changes in response to network structure modifications is not known. The chemical reaction system possesses substructures called buffering structures, which are characterized by a certain topological index being zero. It was proven that the steady-state response to modulation of reaction parameters inside a buffering structure is localized in the buffering structure [1, 2, 3]. In this study, we developed a method to systematically identify the loss or creation of buffering structures induced by the addition of a single degradation reaction from network structure alone. This makes it possible to predict the qualitative and macroscopic changes in regulation that will be caused by the network modification. This method was applied to two reaction systems: the central metabolic system and the mitogen-activated protein kinases (MAPK) signal transduction system. Our method enables identification of reactions that are important for biological functions in living systems. Significance StatementDynamics of complex biological systems have been understood using mathematical models[4, 5, 6, 7]; however, various assumptions are necessary to construct models for large networks such as those found in the life sciences, and discussing the relation between the network structure and its behavior is difficult. Our study using structural sensitivity analysis [1, 2, 3] shows that directly discussing changes in the structure and behavior of a reaction network without making assumptions about kinetics is possible. This enabled the prediction of changes in behavior depending on whether a reaction is present or not and identify reactions that are essentially important for biological behavior.

biophysics↗

bioRxiv2023

Finding regulatory modules of chemical reaction systems

Within a cell, numerous chemical reactions form chemical reaction networks (CRNs), which are the origins of cellular functions. We previously developed a theoretical method called structural sensitivity analysis (SSA) [1], which enables us to determine, solely from the network structure, the qualitative changes in the steady-state concentrations of chemicals resulting from the perturbations to a parameter. Notably, if a subnetwork satisfies specific topological conditions, it is referred to as a buffering structure, and the effects of perturbations to the parameter within the subnetwork are localized to the subnetwork (the law of localization) [2, 3]. A buffering structure can be the origin of modularity in the regulation of cellular functions generated from CRNs. However, an efficient method to search for buffering structures in a large CRN has not yet been established. In this study, we proved the "inverse theorem" of the law of localization, which states that a certain subnetwork exhibiting a confined response range is always a buffering structure. In other words, we are able to identify buffering structures in terms of sensitivities rather than the topological conditions. By leveraging this property, we developed an algorithm to enumerate all buffering structures for a given network by calculating the sensitivity. In addition, using the inverse theorem, we demonstrated that the hierarchy among nonzero responses is equivalent to the hierarchy of buffering structures. Our method will be a powerful tool for understanding the regulation of cellular functions generated from CRNs.

systems biology↗