The Rate of Glucose Oxidation Is Adjusted to Meet the Cells Need for ATP

All enzyme-catalyzed reactions and metabolic pathways are regulated by cells so as to produce the needed amounts of metabolites but not an excess. The primary function of the oxidation of glucose to CO2 via the glycolytic pathway, the pyruvate dehydrogenase reaction, and the citric acid cycle is to produce NADH and FADH2, whose oxidation in mitochondria generates ATP. Operation of the glycolytic pathway and citric acid cycle is continuously regulated, primarily by allosteric mechanisms, to meet the cell's need for ATP (see Chapter 3 for general principles of allosteric control).

Three allosterically controlled glycolytic enzymes play a key role in regulating the entire glycolytic pathway (see Figure 8-4). Hexokinase (step 1) is inhibited by its reaction product, glucose 6-phosphate. Pyruvate kinase (step 10) is inhibited by ATP, so glycolysis slows down if too much ATP is present. The third enzyme, phosphofructokinase-1, which converts fructose 6-phosphate to fructose 1,6-bisphosphate (step 3 ), is the principal rate-limiting enzyme of the glycolytic pathway. Emblematic of its critical role in regulating the rate of glycolysis, this enzyme is allosterically controlled by several molecules (Figure 8-12).

Phosphofructokinase-1 is allosterically inhibited by ATP and allosterically activated by AMP. As a result, the rate of glycolysis is very sensitive to the cell's energy charge, reflected in the ATP:AMP ratio. The allosteric inhibition of phosphofructokinase-1 by ATP may seem unusual, since ATP is also a substrate of this enzyme. But the affinity of the substrate-binding site for ATP is much higher (has a lower Km) than that of the allosteric site. Thus at low concentrations, ATP binds to the catalytic but not to the inhibitory allosteric site, and enzymatic catalysis proceeds at near maximal rates. At high concentrations, ATP also binds to the allosteric site, inducing a conformational change that reduces the affinity of the enzyme for the other substrate, fructose 6-phosphate, and thus inhibits the rate of this reaction and the overall rate of glycolysis.

Another important allosteric activator of phosphofructo-kinase-1 is fructose 2,6-bisphosphate. This metabolite is formed from fructose 6-phosphate by phosphofructokinase-2, an enzyme different from phosphofructokinase-1. Fructose 6-phosphate accelerates the formation of fructose 2,6-bisphosphate, which, in turn, activates phosphofructo-kinase-1. This type of control, by analogy with feedback control, is known as feed-forward activation, in which the abundance of a metabolite (here, fructose 6-phosphate) induces an acceleration in its metabolism. Fructose 2,6-bisphosphate allosterically activates phosphofructokinase-1 in liver cells by decreasing the inhibitory effect of high ATP and by increasing the affinity of phosphofructokinase-1 for one of its substrates, fructose 6-phosphate.

The three glycolytic enzymes that are regulated by allosteric molecules catalyze reactions with large negative AG°' values—reactions that are essentially irreversible under ordinary conditions. These enzymes thus are particularly suitable for regulating the entire glycolytic pathway. Additional control is exerted by glyceraldehyde 3-phosphate dehydro-genase, which catalyzes the reduction of NAD+ to NADH (see Figure 8-4, step 6). If cytosolic NADH builds up owing to a slowdown in mitochondrial oxidation, this reaction will be slowed by mass action. As we discuss later, mitochon-drial oxidation of NADH and FADH2, produced in the glycolytic pathway and citric acid cycle, also is tightly controlled to produce the appropriate amount of ATP required by the cell.

Glucose metabolism is controlled differently in various mammalian tissues to meet the metabolic needs of the organism as a whole. During periods of carbohydrate starvation, for instance, glycogen in the liver is converted directly to glucose 6-phosphate (without involvement of hexokinase). Under these conditions, there is a reduction in fructose 2,6-bisphos-

Glucose

Fructose Phosphof™ct°- Fructose 6-phosphate-_inase_-^ 1,6-bisphosphate--->To pyruvate

'nsulinE Phoohoase-2

'nsulinE Phoohoase-2

ATP ADP

Fructose 2,6-bisphosphate

ATP ADP

Fructose 2,6-bisphosphate

▲ FIGURE 8-12 Allosteric control of glucose metabolism in the cytosol at the level of fructose 6-phosphate. The key regulatory enzyme In glycolysis, phosphofructokinase-1, Is allosterically activated by AMP and fructose 2,6-bisphosphate, which are elevated when the cell's energy stores are low. The enzyme is inhibited by ATP and citrate, which are elevated when the cell is actively oxidizing glucose to CO2. Phosphofructokinase-2 (PFK2) is a bifunctional enzyme: its kinase activity forms fructose

2,6-bisphosphate from fructose 6-phosphate, and its phosphatase activity catalyzes the reverse reaction. Insulin, which is released by the pancreas when blood glucose levels are high, promotes PFK2 kinase activity and thus stimulates glycolysis. At low blood glucose, glucagon is released by the pancreas and promotes PFK2 phosphatase activity in the liver, indirectly slowing down glycolysis. We describe the role of insulin and glucagon in the integrated control of blood glucose levels in Chapter 15.

phate levels and decreased phosphofructokinase-1 activity (see Figure 8-12). As a result, glucose 6-phosphate derived from glycogen is not metabolized to pyruvate; rather, it is converted to glucose by a phosphatase and released into the blood to nourish the brain and red blood cells, which depend primarily on glucose as an energy fuel. (Chapter 13 contains a more detailed discussion of hormonal control of glucose metabolism in liver and muscle.) In all cases, the activity of these regulated enzymes is controlled by the level of small-molecule metabolites, generally by allosteric interactions or by hormonemediated phosphorylation and dephosphorylation.

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