Biochemistry - The Chemical Reactions of Living Cells, Volume 2 - D. Metzler 1980

Biosynthesis: How New Molecules Are Formed
Regulation of Biosynthetic Processes
Substrate Cycles

The question regarding the relationship between the action of Phosphofructokinase and fructose-1,6-diphosphatase [equation (11-19), step g; Fig. 11-11] remains unresolved. Fructose-6-phosphate is phosphorylated to yield fructose diphosphate, which in turn is hydrolyzed to regenerate fructose-6-phosphate. This results in a futile cycle (often referred to as a pointless cycle or substrate cycle) that essentially accomplishes nothing other than the Cleavage of ATP to ADP and P_i (ATPase activity). Cycles of this type are widespread in METABOLISM; however, they typically do not lead to a disastrously rapid depletion of ATP due to the tight Regulation of Metabolic processes. In principle, only one of the two Enzymes catalyzing step g [equation (11-19)] is fully active at any given time. Depending on the metabolic state of The Cell, either degradation can proceed actively with minimal Biosynthesis, or biosynthesis can be active with little degradation. Some of these regulatory mechanisms are illustrated in Fig. 11-11. The intracellular levels of ATP and AMP play a critical role in this process—low AMP concentrations activate the kinase and inhibit the phosphatase. In various species, feedback inhibition may be exerted by ATP, PEP, or citrate. It is quite possible that new regulatory mechanisms involving fructose-1,6-diphosphatase will be discovered in the future.

Other substrate cycles include The conversion of glucose to glucose-6-phosphate and the glycolytic breakdown of glucose-6-phosphate to yield glucose (Fig. 11-11, top left), the Synthesis and degradation of Glycogen (top right), as well as the conversion of phosphoenolpyruvate to Pyruvate and the reverse pathway from pyruvate back to phosphoenolpyruvate via oxaloacetate and malate (which partially takes place within the Mitochondria).

One might expect Cells to minimize substrate flux through such cycles; however, experimental data from rat Liver studies have shown that for the fructose-1,6-diphosphatase–phosphofructokinase cycle, the actual rate is ~3 µmol∙kg^-1∙s^-1 [54]. An unexpectedly high cycling rate has also been observed in the Pyruvate→Oxaloacetate→PEP→Pyruvate cycle [55]. It has been suggested that maintaining a low rate of substrate cycling under conditions of low carbon flux (both toward Glycolysis and Gluconeogenesis) provides the system with heightened sensitivity to allosteric effectors. Theoretical calculations indicate that an increased cycling rate is accompanied by a significantly enhanced response to effectors ([45], Chapter 2). In the presence of appropriate allosteric effectors, substrates can be directed in either direction while maintaining a low net cycling rate.

While substrate cycles are normally under strict control, under pathological conditions they may potentially serve as a source of uncontrolled heat generation (Box 11-E). For example, the thoracic Temperature of a bumblebee during flight must reach at least 30°C. On cold days, insects utilize the substrate cycle catalyzed by phosphofructokinase and fructose diphosphatase to warm their flight Muscles [56].

Box 11-E

Malignant Hyperthermia and Stress-Susceptible Pigs

Cases are known where a patient's temperature begins to rise uncontrollably during surgery, and even extraordinary measures fail to save the individual from rapid death. This malignant hyperthermia syndrome is associated with the action of halogenated anesthetic agents^a,b. However, patients frequently show no prior indication of heightened sensitivity to anesthesia, leading to the hypothesis that underlying defects in the patient's Muscle Tissues may be involved. Biochemical studies aimed at elucidating the causes of hyperthermia syndrome were greatly facilitated by the discovery of this syndrome in specific breeds of pigs, manifested during transport. It was found that such stress-susceptible pigs undergo a sharp increase in body temperature during stress, accompanied by muscle rigidity and a severe depletion of ATP within the Muscle tissue.

According to available experimental data^b, the cause of hyperthermia lies in the impairment of a substrate cycle (Section E, 6) involving enzymes such as phosphofructokinase and fructose diphosphatase, which are responsible for the sudden Hydrolysis of ATP and the release of heat. Although the exact mechanism by which anesthetics trigger this response in humans remains unclear, it is hypothesized that the interaction of the anesthetic with cell membranes—disrupting the normal function of hormonal regulatory systems—plays a crucial role. Another possible explanation relates to The Effect of anesthetics on mitochondrial membranes^c.

^a Gordon R. A., Britt B. A., Katow W., eds., International Symposium on Malignant Hyperthermia, Thomas, Springfield, Illinois, 1973.

^b Clark M. G., Williams C. H., Pfeifer W. F., Bloxham D. P., Holland P. C., Taylor C. A., Lardy H. A., Nature (London), 245, 99–101 (1973).

^c Eikelenboom G., Sybesma W., J. Anim. Sci., 38, 504–506 (1974).