Harpers

Glycolysis & the Oxidationof Pyruvate 17Peter A. Mayes, PhD, DSc, & David A. Bender, PhDBIOMEDICAL IMPORTANCEMost tissues have at least some requirement for glucose.In brain, the requirement is substantial. Glycolysis, themajor pathway for glucose metabolism, occurs in thecytosol of all cells. It is unique in that it can function eitheraerobically or anaerobically. Erythrocytes, whichlack mitochondria, are completely reliant on glucose astheir metabolic fuel and metabolize it by anaerobic glycolysis.However, to oxidize glucose beyond pyruvate(the end product of glycolysis) requires both oxygenand mitochondrial enzyme systems such as the pyruvatedehydrogenase complex, the citric acid cycle, and therespiratory chain.Glycolysis is both the principal route for glucosemetabolism and the main pathway for the metabolismof fructose, galactose, and other carbohydrates derivedfrom the diet. The ability of glycolysis to provide ATPin the absence of oxygen is especially important becauseit allows skeletal muscle to perform at very high levelswhen oxygen supply is insufficient and because it allowstissues to survive anoxic episodes. However, heart muscle,which is adapted for aerobic performance, has relativelylow glycolytic activity and poor survival underconditions of ischemia. Diseases in which enzymes ofglycolysis (eg, pyruvate kinase) are deficient are mainlyseen as hemolytic anemias or, if the defect affectsskeletal muscle (eg, phosphofructokinase), as fatigue.In fast-growing cancer cells, glycolysis proceeds at ahigher rate than is required by the citric acid cycle,forming large amounts of pyruvate, which is reduced tolactate and exported. This produces a relatively acidiclocal environment in the tumor which may have implicationsfor cancer therapy. The lactate is used for gluconeogenesisin the liver, an energy-expensive process responsiblefor much of the hypermetabolism seen incancer cachexia. Lactic acidosis results from severalcauses, including impaired activity of pyruvate dehydrogenase.136GLYCOLYSIS CAN FUNCTION UNDERANAEROBIC CONDITIONSWhen a muscle contracts in an anaerobic medium, ie,one from which oxygen is excluded, glycogen disappearsand lactate appears as the principal end product.When oxygen is admitted, aerobic recovery takes placeand lactate disappears. However, if contraction occursunder aerobic conditions, lactate does not accumulateand pyruvate is the major end product of glycolysis.Pyruvate is oxidized further to CO 2 and water (Figure17–1). When oxygen is in short supply, mitochondrialreoxidation of NADH formed from NAD + during glycolysisis impaired, and NADH is reoxidized by reducingpyruvate to lactate, so permitting glycolysis to proceed(Figure 17–1). While glycolysis can occur underanaerobic conditions, this has a price, for it limits theamount of ATP formed per mole of glucose oxidized,so that much more glucose must be metabolized underanaerobic than under aerobic conditions.THE REACTIONS OF GLYCOLYSISCONSTITUTE THE MAIN PATHWAYOF GLUCOSE UTILIZATIONThe overall equation for glycolysis from glucose to lactateis as follows:Glucos e + 2ADP + 2Pi→ 2L( + ) − Lactate + 2ATP + 2H 2 OAll of the enzymes of glycolysis (Figure 17–2) arefound in the cytosol. Glucose enters glycolysis by phosphorylationto glucose 6-phosphate, catalyzed by hexokinase,using ATP as the phosphate donor. Underphysiologic conditions, the phosphorylation of glucoseto glucose 6-phosphate can be regarded as irreversible.Hexokinase is inhibited allosterically by its product,glucose 6-phosphate. In tissues other than the liver andpancreatic B islet cells, the availability of glucose for