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1. Alternate Pathways tor Glycogen Synthesis and Degradation:
An excellent example of allosteric enzyme regulation of metabolic processes is provided by the interrelationship in animals between the metabolic pathways that result in:
(1) The synthesis of glycogen from glucose and
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(2) The oxidation of glucose to CO2 and water.
Nearly all of the energy-consuming processes in the body proceed at the expense of ATP and much of this ATP is derived through the oxidation of glucose. During periods of elevated activity (e.g., exercise), glycogen is broken down to yield glucose, which then enters the metabolic pathway converting it to CO2 and water, with consequent generation of ATP. In contrast, during periods of rest or low energy demand, absorbed glucose is converted to glycogen.
Three of the enzymes involved in glucose metabolism are allosteric; these are phosphofructokinase (an enzyme required in the series of reactions that convert glucose-6-phosphate to CO2 and water), glycogen synthetase (involved in the incorporation of glucose-l-phosphate into glycogen), and glycogen phosphorylase (which removes glucose as glucose-l-phosphate from glycogen during glycogen catabolism).
When ATP levels are high and no major consumption of energy is taking place in the body, glucose is diverted into glycogen (i.e., “glycogenesis” predominates). This is achieved because ATP acts as a negative effector of phosphofructokinase and glycogen phosphorylase and as a positive effector, along with glucose-6-phosphate, of glycogen synthetase (Fig. 11-8a).
When the ATP level falls (e.g., during exercise) and there is an increased demand for ATP, glycogen synthesis is halted as absorbed glucose is directly consumed in the production of ATP and additional glucose is made available through the catabolism of glycogen (i.e., “glycogenolysis”). This pathway is activated by the positive effects on phosphofructokinase and glycogen phosphorylase of the ATP precursor, AMP.
The hormone epinephrine, secreted into the bloodstream during periods of great activity, also has an effect on these metabolic pathways in muscle and in liver. When epinephrine in the bloodstream reaches the muscles, it binds to the surface of the muscle cells and promotes the synthesis of cyclic AMP (cAMP) by the enzyme adeny Icy close.
The cAMP then allosterically activates a second enzyme (protein kinase), which ultimately activates glycogen phosphorylase but inactivates glycogen synthetase (Fig. 11-8b). This phenomenon is also considered with the functions of hormones and the role of protein phosphorylation as a metabolic regulatory mechanism.
The pathways described above illustrate the mechanisms for turning allosteric enzymes on and off. In the absence of such mechanisms, both pathways would simultaneously be active so that their effects cancel one another—a most unproductive state! Allosterism thus provides a basis for regulating the levels of activity of related metabolic pathways.
The Regulation of Amino Acid Synthesis:
Escherichia coli provide a clear example of control of divergent metabolic pathways by feedback inhibition. An outline of the metabolic pathways for the synthesis of three amino acids is shown in Figure 11-9. Lysine, methionine, and threonine are each synthesized from aspartate and each may be utilized in protein synthesis.
Without metabolic controls, the consumption or utilization of any one of these amino acids would stimulate the pathways and cause unneeded synthesis of the unused amino acids as well as the one utilized. Such an unregulated system would consume vital resources and energy; both factors could have survival implications to the organism and evolutionary consequences to the species.
However, in E. coli, the allosteric regulatory mechanisms are most effective. The accumulation of each amino acid produces a feedback inhibition of the first enzyme in the specific branch of the pathway leading to the synthesis of that amino acid. In Figure 11-9, this negative effect is shown by dashed lines.
Moreover, an additional level of regulation is achieved through effects on the enzyme aspartokinase, which catalyzes and phosphorylation of aspartate. This enzyme exists in three forms (i.e., there are three isozymes), symbolized in Figure 11-9 by using three separate arrows to show the conversion of aspartate to aspartylphosphate.
One of the isozymes is specifically and completely inhibited by threonine; the second (which is present only in small amounts) is specifically inhibited by homoserine; and the third isozyme is specifically inhibited by lysine. In addition, synthesis of the latter isozyme is repressed by lysine. (Repression is a regulatory mechanism that reduces the number of enzyme molecules in the cell.
