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Biomedical subjects

A Goldbeter

Publications and source records attributed to A Goldbeter.

At least 73 records · Page 4Linked to original sources
PubMed1984

Onset of birhythmicity in a regulated biochemical system.

We analyze the onset of multiple oscillatory regimes in a two-variable biochemical model previously proposed for glycolytic oscillations. The model, based on the activation of an allosteric enzyme by a reaction product, is modified by introduction of recycling of product into the substrate. This modification creates the conditions for birhythmicity in which two stable oscillatory regimes coexist under the same conditions. The detailed route by which birhythmicity develops from a single oscillatory regime is elucidated by means of bifurcation diagrams. It is shown that birhythmicity provides added sensitivity to the oscillatory system as the same type of perturbation may produce a switch from one periodic regime to the other and back, when applied at the appropriate phase of each of the two oscillations.

Animals↗
PubMed1983

Temporal self-organization in biochemical systems: periodic behavior vs. chaos.

The patterns of temporal self-organization in regulated biochemical systems are examined. Simple periodic oscillations are the most frequent type of such organization, as exemplified by glycolytic oscillations in yeast and muscle and by the periodic synthesis of adenosine 3',5'-cyclic monophosphate in Dictyostelium discoideum amoebas. These phenomena originate, respectively, from the periodic operation of the product-activated phosphofructokinase and adenylate cyclase reactions. The analysis of a model for a multiply regulated biochemical system shows more complex oscillatory phenomena, e.g., the coexistence between two stable periodic regimes for the same set of parameter values (birhythmicity) and chaos. The latter phenomenon of aperiodic oscillations occurs in a narrow range of parameter values and is much less frequent than simple or complex periodic behavior. It is suggested that a sufficient condition for the occurrence of birhythmicity and chaos in a regulated biological system subjected to a constant environment (i.e., in the absence of periodic forcing) may be the simultaneous presence and interaction of two mechanisms capable of producing oscillations.

Animals↗
PubMed1982

Birhythmicity, chaos, and other patterns of temporal self-organization in a multiply regulated biochemical system.

We analyze on a model biochemical system the effect of a coupling between two instability-generating mechanisms. The system considered is that of two allosteric enzymes coupled in series and activated by their respective products. In addition to simple periodic oscillations, the system can exhibit a variety of new modes of dynamic behavior; coexistence between two stable periodic regimes (birhythmicity), random oscillations (chaos), and coexistence of a stable periodic regime with a stable steady state (hard excitation) or with chaos. The relationship between these patterns of temporal self-organization is analyzed as a function of the control parameters of the model. Chaos and birhythmicity appear to be rare events in comparison with simple periodic behavior. We discuss the relevance of these results with respect to the regularity of most biological rhythms.

Enzymes↗
PubMed1981

Metabolic oscillations in biochemical systems controlled by covalent enzyme modification.

We analyze the conditions under which sustained oscillations develop in a biochemical system regulated autocatalytically by reversible, covalent enzyme modification. The analysis applies, for example, to the situation where adenylate cyclase (or guanylate cyclase) is activated through phosphorylation by a cAMP (or cGMP)-dependent protein kinase. The model then provides a non-allosteric mechanism for the periodic generation of cAMP or cGMP pulses. For certain parameter values close to those that produce oscillations, the system is excitable since it can amplify in a pulsatory manner suprathreshold perturbations. The results on excitable and oscillatory behavior are discussed in relation with the mechanism of cAMP relay and oscillation in the slime mold Dictyostelium discoideum.

Adenylyl Cyclases↗
PubMed1981

An amplified sensitivity arising from covalent modification in biological systems.

The transient and steady-state behavior of a reversible covalent modification system is examined. When the modifying enzymes operate outside the region of first-order kinetics, small percentage changes in the concentration of the effector controlling either of the modifying enzymes can give much larger percentage changes in the amount of modified protein. This amplification of the response to a stimulus can provide additional sensitivity in biological control, equivalent to that of allosteric proteins with high Hill coefficients.

Climate↗
PubMed1980

Control of developmental transitions in the cyclic AMP signalling system of Dictyostelium discoideum.

In the first few hours after starvation, the developing cAMP secretory system in Dictyostelium discoideum has been observed to be successively in one of four states: (a) quiescent, (b) excitable (capable of relay), (c) autonomously oscillating, and (d) secreting at a high steady level. A theoretical model is presented which demonstrates that the proximal cause of the transitions between different types of behavior may be slow changes in the activities of the enzymes adenylate cyclase and phosphodiesterase. These changes affect the stability properties of the steady state admitted by the cAMP signalling system. Sustained oscillations develop when the steady state is unstable, whereas relay of cAMP signals occurs upon perturbation of a stable steady state for parameter values close to those which produce oscillations. The developmental path suggested in the adenylate cyclase-phosphodiesterase space for the sequential transitions compares with the time course observed for the synthesis of these enzymes after starvation. It is suggested that there is general significance for the understanding of differentiation in the example given of a state-point following a developmental path in parameter space, moving from one behavioral domain to another, and thereby bringing about shifts in qualitative behavior.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Allosteric oscillatory enzymes: influence of the number of protomers on metabolic periodicities.

The study of a concerted allosteric model for an enzyme activated by the reaction product shows that this system can generate sustained metabolic oscillations regardless of the number of protomers constituting the enzyme. The analysis extends the results previously obtained in a dimeric model for the phosphofructokinase reaction which produces glycolytic periodicities. When the substrate and product concentrations evolve on comparable time scales, the amplitude of oscillations significantly drops as the number of enzyme subunits evolves from 2 to 8. The width of the domain of substrate injection rates which produce oscillations and the periodic variation in enzyme activity also depend on the number of protomers and on the time scale structure of the system. Theoretical predictions are compared with the experiments on glycolytic oscillations in yeast and muscle, and with the structural characteristics of phosphofructokinase. The results are also discussed in relation with the mechanism of cyclic AMP oscillations in the slime mold Dictyostelium discoideum.

Allosteric Regulation↗
PubMed1977

Unified mechanism for relay and oscillation of cyclic AMP in Dictyostelium discoideum.

A modified version of an allosteric model for adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] previously analyzed for sustained oscillations of adenosine 3':5'-cyclic monophosphate (cAMP) in Dictyostelium discoideum [Goldbeter, A. (1975) Nature 253, 540-542] is examined to see whether it can account for the relay of cAMP pulses. Oscillations occur around a nonequilibrium, unstable stationary state when system parameters are in a certain domain. It is found that relay can occur outside this domain, in a restricted set of parameter values for which the solution ultimately tends to a stable steady state. A suprathreshold level of extracellular cAMP is needed to elicit relay which consists in a pulsatory synthesis of intracellular cAMP. Theoretical predictions are compared with the results of experiments on cAMP relay and oscillation in aggregation-competent cells of D. discoideum. The model suggests an explanation for the emergence of aggregation centers and for a sequence of developmental events observed in interphase amoebae.

Adenylyl Cyclases↗
PubMed1976

On the role of enzyme cooperativity in metabolic oscillations: analysis of the Hill coefficient in a model for glycolytic periodicities.

The role of enzyme cooperativity in the mechanism of metabolic oscillations is analyzed in a concerted allosteric model for the phosphofructokinase reaction. This model of a dimer enzyme activated by the reaction product accounts quantitatively for glycolytic periodicities observed in yeast and muscle. The Hill coefficient characteristic of enzyme-substrate interactions is determined in the model, both at the steady state and in the course of sustained oscillations. Positive cooperativity is a prerequisite for periodic behavior. A necessary condition for oscillation in a dimer K system is a Hill coefficient larger than 1.6 at the unstable stationary state. The analysis suggests that positive as well as negative effectors of phosphofructokinase inhibit glycolytic oscillations by inducing a decrease in enzyme cooperativity. The results are discussed with respect to glycolytic and other metabolic periodicities.

Allosteric Regulation↗
PubMed1976

Kinetic cooperativity in the concerted model for allosteric enzymes.

The cooperativity of enzyme-substrate interactions is investigated in the concerted allosteric model of Monod, Wyman and Changeux. The general case of K-V systems is considered, in which the two protomer conformational states R and T postulated in the theory differ in catalytic and binding properties. An expression for the Hill coefficient nH defined with respect to the asymptotic velocity V infinity to is analyzed in conditions which exclude substrate inhibition. Kinetic cooperativity is always positive (nH greater than 1) in the case of a dimer enzyme, and in the case of an inactive T state. Slight kinetic negative cooperativity (nH less than 1) occurs under restrictive conditions for larger numbers of protomers when the substrate binds significantly to the less active state of the enzyme, but the phenomenon remains negligible for trimers and tetramers. These conclusions differ from those obtained [A. Goldbeter, J. Mol.Biol.90 (1974) 185] with the Hill coefficient based on the absolute maximum velocity, which may exceed the experimental value V infinity to in K-V systems. The results extend those of Paulus and DeRiel [J. Mol. Biol. 97 (1975) 667] and support the view that in most cases, negative cooperativity is not compatible with a mechanism based on a concerted and conservative allosteric transition. The Hill coefficients for binding and catalysis are compared in K-V systems.

Allosteric Regulation↗