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INTRODUCTION

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OBJECTIVES

After studying this chapter, you should be able to:

  • Describe the pathway of glycolysis and its control, and explain how glycolysis can operate under anaerobic conditions.

  • Describe the reaction of pyruvate dehydrogenase and its regulation.

  • Explain how inhibition of pyruvate metabolism leads to lactic acidosis.

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BIOMEDICAL IMPORTANCE

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Most tissues have at least some requirement for glucose. In the brain, the requirement is substantial, and even in prolonged fasting the brain can meet no more than about 20% of its energy needs from ketone bodies. Glycolysis, the major pathway for glucose metabolism, occurs in the cytosol of all cells. It can function either aerobically or anaerobically, depending on the availability of oxygen and the electron transport chain. Erythrocytes, which lack mitochondria, are completely reliant on glucose as their metabolic fuel, and metabolize it by anaerobic glycolysis. However, to oxidize glucose beyond pyruvate (the end product of glycolysis) requires both oxygen and mitochondrial enzyme systems: the pyruvate dehydrogenase complex, the citric acid cycle (see Chapter 16), and the respiratory chain (see Chapter 13).

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Glycolysis is the principal route for carbohydrate metabolism. The ability of glycolysis to provide ATP in the absence of oxygen is especially important, because this allows skeletal muscle to perform at very high levels of work output when oxygen supply is insufficient, and it allows tissues to survive anoxic episodes. However, heart muscle, which is adapted for aerobic performance, has relatively low glycolytic activity and poor survival under conditions of ischemia. Diseases in which enzymes of glycolysis (eg, pyruvate kinase) are deficient are mainly seen as hemolytic anemias or, if the defect affects skeletal muscle (eg, phosphofructokinase), as fatigue. In fast-growing cancer cells, glycolysis proceeds at a high rate, forming large amounts of pyruvate, which is reduced to lactate and exported. This produces a relatively acidic local environment in the tumor, which may have implications for cancer therapy. The lactate is used for gluconeogenesis in the liver (Chapter 19), an energy-expensive process, which is responsible for much of the hypermetabolism seen in cancer cachexia. Lactic acidosis results from various causes, including impaired activity of pyruvate dehydrogenase, especially in thiamin (vitamin B1) deficiency.

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GLYCOLYSIS CAN FUNCTION UNDER ANAEROBIC CONDITIONS

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Early in the investigations of glycolysis it was realized that fermentation in yeast was similar to the breakdown of glycogen in muscle. It was noted that when a muscle contracts in an anaerobic medium glycogen disappears and lactate appears. When oxygen is admitted, aerobic recovery takes place and lactate is no longer produced. However, if muscle contraction occurs under aerobic conditions, lactate does not accumulate and pyruvate is the major end product of glycolysis. Pyruvate is oxidized further to CO2 and water (Figure 17–1). When oxygen is in short supply, mitochondrial reoxidation of NADH formed during glycolysis is impaired, and NADH is reoxidized ...

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