Regulating Energy Pathways

We have described the relationships between metabolic pathways and noted that these pathways work together to provide homeostasis in the cell and organism. But how does the cell regulate interconversions between these pathways to maintain constant metabolic pools? Consider what happens to the starch in your burger bun. In the digestive system, starch is hydrolyzed to glucose which enters the blood for distribution to the rest of the body. Before this happens, however, a “decision” must be made: Is there already enough glucose in the blood to supply the body’s needs? If there is, the excess glucose is converted to stored glycogen in the liver. If not enough glucose is supplied by food, liver glycogen is broken down or other molecules are used to make glucose by gluconeogenesis. The end result is that the level of glucose in the blood is remarkably constant. For now, it is important to realize that the interconversions of glucose involve many steps, each catalyzed by an enzyme, and it is here that controls often reside. Glycolysis, the citric acid cycle, and the respiratory chain are regulated by allosteric controlof the enzymes involved. These negative and positive feedback control mechanisms are used at many points in the energyharvesting pathways, which are summarized in Figure . The main control point in glycolysis is the enzyme phosphofructokinase (reaction 3). This enzyme is allosterically inhibited by ATP and activated by ADP or AMP. As long as fermentation proceeds, yielding a relatively small amount of ATP, phosphofructokinase operates at full efficiency. But when cellular respiration begins producing 18 times more ATP than fermentation does, the abundant ATP allosterically inhibits the enzyme, and the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate declines, as does the rate of glucose utilization.

The main control point in the citric acid cycle is the enzyme isocitrate dehydrogenase, which converts isocitrate to ketoglutarate (reaction 3). NADH + H+ and ATP are feedback inhibitors of this reaction; ADP and NAD+ are activators. If too much ATP is accumulating, or if NADH + H+ is being produced faster than it can be used by the respiratory chain, the conversion of isocitrate is slowed, and the citric acid cycle is essentially shut down. A shutdown of the citric acid cycle would cause large amounts of isocitrate and citrate to accumulate if the conversion of acetyl CoA to citrate were not also slowed by abundant ATP and NADH + H+. However, a certain excess of citrate does accumulate, and this excess acts as an additional negative feedback inhibitor to slow the fructose 6-phosphate reaction early in glycolysis. Consequently, if the citric acid cycle has been slowed down because of abundant ATP (and not because of a lack of oxygen), glycolysis is shut down as well. Both processes resume when the ATP level falls and they are needed again. Allosteric control keeps these processes in balance. Another control point involves a method for storing excess acetyl CoA. If too much ATP is being made and the citric acid cycle shuts down, the accumulation of citrate switches acetyl CoA to the synthesis of fatty acids for storage. This is one reason why people who eat too much accumulate fat. These fatty acids may be metabolized later to produce more acetyl CoA.