Abstract

The signal transduction system, which is known as a regulatory mechanism for biochemical reaction systems in the cell, has been the subject of intensive research in recent years, and its design methods have become necessary from the viewpoint of synthetic biology. We proposed the partition representation of enzymatic reaction networks consisting of post-translational modification reactions such as phosphorylation, which is an important basic component of signal transduction systems, and attempted to find enzymatic reaction networks with bistability to demonstrate the effectiveness of the proposed representation method. The partition modifiers can be naturally introduced into the partition representation of enzymatic reaction networks when applied to search. By randomly applying the partition modifiers as appropriate, we searched for bistable and resettable enzymatic reaction networks consisting of four post-translational modification reactions. The proposed search algorithm worked well and we were able to find various bistable enzymatic reaction networks, including a typical bistable enzymatic reaction network with positive auto-feedbacks and mutually negative regulations. Since the search algorithm is divided into an evaluation function specific to the characteristics of the enzymatic reaction network to be searched and an independent algorithm part, it may be applied to search for dynamic properties such as biochemical adaptation, the ability to reset the biochemical state after responding to a stimulus, by replacing the evaluation function with one for other characteristics.

Highlights

  • The intracellular signal transduction system functions as a mechanism to control cell proliferation, apoptosis, differentiation, and homeostasis, and its malfunction is thought to be one of the substantial causes of cancer formation for cells

  • The variations in the total concentration of enzymes containing the input chemical species were set to 21 discrete values of O = 2−5, 2−4.5, . . ., 25. These values, as well as the reaction rate constants to be set as ν, are set to include approximately the values reported for the kinases that make up the MAPK cascade, which is known to be a typical cellular signaling system

  • We have shown that an enzymatic reaction network composed of post-translational modification reactions can be represented by a partition of the set whose elements are the enzymes, substrates, and products

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Summary

Introduction

The intracellular signal transduction system functions as a mechanism to control cell proliferation, apoptosis, differentiation, and homeostasis, and its malfunction is thought to be one of the substantial causes of cancer formation for cells. The regulatory mechanism of signal transduction systems is closely related to the mechanism of action of drugs, such as anticancer drugs, and has been the subject of extensive research in recent years. From the viewpoint of synthetic biology, which has been the focus of much research in recent years, design methods for signal transduction systems have become necessary. Because biochemical reactions are nonlinear, it is difficult to establish theoretical analysis. The partition representation of enzymatic reaction networks

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