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Bistability in the isocitrate dehydrogenase reaction: an experimentally based theoretical study
G M Guidi1, M F Carlier, A Goldbeter
1Faculté des Sciences, Université Libre de Bruxelles, Brussels, Belgium.
Biophysical Journal
|March 25, 1998
Summary
The isocitrate dehydrogenase (IDH) enzyme system can exist in two stable states, controlled by the timing of diaphorase addition. This bistability in enzyme kinetics is theoretically modeled and experimentally confirmed.
Area of Science:
- Biochemistry
- Enzyme Kinetics
- Systems Biology
Background:
- Isocitrate dehydrogenase (IDH) exhibits product activation by NADPH, which is competitively inhibited by NADP+.
- IDH and diaphorase form a bienzymatic system where diaphorase converts NADPH to NADP+.
- This coupling can lead to multiple stable states in the system's dynamics.
Purpose of the Study:
- To theoretically and numerically analyze the IDH-diaphorase bienzymatic system.
- To confirm the occurrence of bistability based on experimental parameter values.
- To determine conditions and critical factors influencing the system's stable states.
Main Methods:
- Theoretical modeling of the IDH-diaphorase system based on IDH regulatory properties.
- Numerical analysis to simulate system behavior under varying conditions.
- Analysis extended to scenarios with substrate consumption (isocitrate).
Main Results:
- Confirmed bistability in the IDH-diaphorase system for experimentally relevant parameters.
- Identified dependence of steady states (low/high NADPH) on diaphorase addition timing.
- Derived an expression for critical time (t*) determining the final steady state.
Conclusions:
- The IDH-diaphorase system demonstrates bistability, with two distinct NADPH concentration states.
- System behavior is sensitive to initial conditions, specifically the timing of diaphorase introduction.
- Bistability is transient when the isocitrate substrate is consumed without regeneration.