Glycolytic oscillator

A prominent puzzle related to glycolytic oscillations in yeast is the question of their physiological significance. A number of diverse hypothesis have been... 

The negative feedback in glycolysis, induced by substrate inhibition of lumped PFK HK reaction, thus fulfills an important functional role but concomitantly opens the possibility of sustained oscillations. In particular, because glycolytic oscillations have no obvious physiological role and are only observed under rather specific experimental conditions, it is plausible that they are merely an unavoidable side effect of regulatory interactions that are optimized for other purposes. 

A. Goldbeter and R. Lefever, Dissipative structures for an allosteric model Application to glycolytic oscillations. Biophys. J. 12, 1302 1315 (1972). 

M. Bier, B. M. Bakker, and H. V. Westerhoff, How yeast cells synchronize their glycolytic oscillations A perturbation analytic treatment. Biophys. J. 78, 1087 1093 (2000). 

Some of the main examples of biological rhythms of nonelectrical nature are discussed below, among which are glycolytic oscillations (Section III), oscillations and waves of cytosolic Ca + (Section IV), cAMP oscillations that underlie pulsatile intercellular communication in Dictyostelium amoebae (Section V), circadian rhythms (Section VI), and the cell cycle clock (Section VII). Section VIII is devoted to some recently discovered cellular rhythms. The transition from simple periodic behavior to complex oscillations including bursting and chaos is briefly dealt with in Section IX. Concluding remarks are presented in Section X. 

Glycolytic oscillations in yeast cells provided one of the first examples of oscillatory behavior in a biochemical system. They continue to serve as a prototype for cellular rhythms. This oscillatory phenomenon, discovered some 40 years ago [36, 37] and still vigorously investigated today [38], was important in several respects First, it illustrated the occurrence of periodic behavior in a key metabolic pathway. Second, because they were soon observed in cell extracts, glycolytic oscillations provided an instance of a biochemical clock amenable to in vitro studies. Initially observed in yeast cells and extracts, glycolytic oscillations were later observed in muscle cells and evidence exists for their occurrence in pancreatic p-cells in which they could underlie the pulsatile secretion of insulin [39]. 

The molecular mechanism of glycolytic oscillations has been discussed for long [31, 38, 40-42]. Because glycolysis represents a system of enzymatic reactions coupled through different intermediates such as ATP and NADH,... 

The question of how glycolytic oscillations synchronize in a population of yeast cells is of great current interest [51]. It has long been known that the oscillations disappear in a yeast suspension when the cell density decreases below a critical value. Acetaldehyde appears to act as synchronizing factor in such suspensions [52], and the way it allows cells to synchronize is being... 

Studied in both an experimental and theoretical manner. The link between glycolytic oscillations and the pulsatile secretion of insulin in pancreatic p cells [53] is another topic of current concern. Models for the latter phenomenon rely on the coupling between intracellular metabolic oscillations and an ionic mechanism generating action potentials. Such coupling results in bursting oscillations of the membrane potential, which are known to accompany insulin secretion in these cells [54, 55]. 

The three best-known examples of biochemical oscillations were found during the decade 1965-1975 [40,41]. These include the peroxidase reaction, glycolytic oscillations in yeast and muscle, and the pulsatile release of cAMP signals in Dictyostelium amoebae (see Section V). Another decade passed before the development of Ca " " fluorescent probes led to the discovery of oscillations in intracellular Ca +. Oscillations in cytosolic Ca " " have since been found in a variety of cells where they can arise spontaneously, or after stimulation by hormones or neurotransmitters. Their period can range from seconds to minutes, depending on the cell type [56]. The oscillations are often accompanied by propagation of intracellular or intercellular Ca " " waves. The importance of Ca + oscillations and waves stems from the major role played by this ion in the control of many key cellular processes—for example, gene expression or neurotransmitter secretion. 

To give rise to oscillatory behavior instead of a biochemical explosion, selfamplification must, however, be coupled to a limiting process. Such a limiting process can be viewed as a form of negative feedback because it occurs as a consequence of the positive feedback that precedes it. Thus, in the case of glycolytic oscillations, the activation of phosphofructokinase by a reaction product is followed by a counteracting fall in the rate of the enzymatic reaction, due to the enhanced substrate consumption associated with enzyme activation. In Ca + pulsatile signaling, the explosive rise in cytosolic Ca + due... 

P. Richard, B. M. Bakker, B. Teusink, K. Van Dam, H. V. Westerhoff, Acetaldehyde mediates the synchronization of sustained glycolytic oscillations in populations of yeast cells. Eur. 

MEYERHOF OXIDATION QUOTIENT See also specific enzyme of glycolysis GLYCOLYTIC OSCILLATION GLYCOSIDASES,... 

In a series of experiments we have tested the type and range of entrainment of glycolytic oscillations by a periodic source of substrate realizing domains of entrainment by the fundamental frequency, one-half harmonic and one-third harmonic of a sinusoidal source of substrate. Furthermore, random variation of the substrate input was found to yield sustained oscillations of stable period. The demonstration of the subharmonic entrainment adds to the proof of the nonlinear nature of the glycolytic oscillator, since this behavior is not observed in linear systems. A comparison between the experimental results and computer simulations furthermore showed that the oscillatory dynamics of the glycolytic system can be described by the phosphofructokinase model. 

Goldbeter, A. and Nicolis, G. (1976). An allosteric enzyme model with positive feedback applied to glycolytic oscillations. J. Theor. Biol., 4, 65-160. 

Fig. 3.4 The glycolytic pathway produces NADH which under regular conditions is oxidized to NAD+ while reducing acetaldehyde (ACA) to ethanol (EtOH), thereby in turn reducing NAD+ in order to keep hexose catabolism running. The actual cytosolic NADH concentration is determined by the respective conversion rates of the enzymes involved in the oxidation and regeneration of the compound. If these enzymes convert additional non-natural substrates (xenobiotics, i.e. drugs), the conversion rate changes. As a consequence, the cytosolic NADH concentration differs from the natural condition. Furthermore, if a xenobiotic acts as an enzyme inhibitor, e.g. for ADH, then NAD+ regeneration is substantially affected, which eventually results in altered cytosolic NADH concentration. Therefore the presence of a xenobiotic in the cell is conceivably a perturbation factor. Under the conditions where glycolytic oscillations...

The upshot on the oscillation is a direct measure for the extent of perturbation on the metabolic network upon the uptake of a PAC. Glycolytic oscillations that are systematically perturbed by altered environmental conditions, i.e. exposure to the xenobiotic, constitute a direct and easily accessible measure of the intracellular behavior since the frequency and amplitude of oscillating metabolite concentrations and fluxes depend on both the perturbation and on most intracellular processes due to the coupled energy (ATP) and redox (NADH) balances (Fig. 3.4). 

Due to their significance in affecting glycolytic oscillations, these pathways are discussed shortly. 

Wolf, J. Heinrich, R. Effect of cellular interaction on glycolytic oscillations in yeast a theoretical investigation. Biochem J 2000, 345 321-334. 

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