Anaerobic glycolysis, which produces lactic acid, occurs in cells lacking mitochondria or deprived of sufficient oxygen (O2). Glucose is transported across membranes by one of the 14 isoforms of glucose transporter (GLUT). GLUT-1 is abundant in red blood cells (RBC) and the brain, GLUT-4 (insulin dependent) in muscle and adipose tissue, and GLUT-2 in the liver, kidneys, and pancreatic β cells. The oxidation of glucose to pyruvate (glycolysis) involves an energy-investment phase where ATP is used to synthesize phosphorylated intermediates, and an energy-generation phase where ATP is produced through substrate-level phosphorylation. Hexokinase (found in most tissues) or glucokinase (found in liver cells and pancreatic β cells) phosphorylates glucose during the energy-investment phase. Hexokinase has a high affinity for glucose but a low maximal velocity, while glucokinase has a high affinity and a high maximal velocity. Glucokinase is regulated indirectly by fructose 6-phosphate and glucose via glucokinase regulatory protein. Glucose 6-phosphate is converted to fructose 6-phosphate, which is then phosphorylated to fructose 1,6-bisphosphate by phosphofructokinase-1 (PFK-1). PFK-1 is allosterically inhibited by ATP and citrate, and activated by AMP. Fructose 2,6-bisphosphate, synthesized by bifunctional phosphofructokinase-2 (PFK-2), is the most potent allosteric activator of PFK-1 and its production is increased by insulin and decreased by glucagon in the liver. Two ATP molecules are consumed during this phase of glycolysis. Fructose 1,6-bisphosphate is cleaved to form two trioses, which are further metabolized in the glycolytic pathway to produce pyruvate. This phase generates four ATP molecules and two nicotinamide adenine dinucleotide (NADH) molecules per glucose molecule. The final step in pyruvate synthesis from phosphoenolpyruvate is catalyzed by pyruvate kinase (PK). PK is allosterically activated by fructose 1,6-bisphosphate and is covalently inhibited by glucagon via the cAMP pathway in the hepatic isozyme. Deficiency of PK is responsible for the majority of inherited defects in glycolytic enzymes, leading to mild-to-severe chronic nonspherocytic hemolytic anemia. Insulin and glucose enhance the transcription of glycolytic genes. In anaerobic glycolysis, NADH is reoxidized to NAD+ by the reduction of pyruvate to lactate, a process catalyzed by lactate dehydrogenase. This occurs in cells lacking mitochondria, such as RBC, and in tissues with high NADH production compared to the oxidative capacity of the respiratory chain, such as exercising muscle. Elevated concentrations of lactate in the plasma (lactic acidosis) occur in conditions like circulatory system collapse or shock. Pyruvate can also be oxidatively decarboxylated to acetyl CoA by pyruvate dehydrogenase, carboxylated to oxaloacetate (an intermediate of the TCA cycle) by pyruvate carboxylase, or reduced to ethanol by microbial pyruvate decarboxylase.
Fig. 8.25). Anaerobic glycolysis, in which lactic acid is the end product, occurs in cells that lack mitochondria and in cells deprived of sufficient O2. Glucose is passively transported across membranes by 1 of 14 glucose transporter (GLUT) isoforms. GLUT-1 is abundant in RBC and the brain, GLUT-4 (which is insulin dependent) in muscle and adipose tissue, and GLUT-2 in the liver, kidneys, and pancreatic β cells. The oxidation of glucose to pyruvate (glycolysis, see Fig. 8.25) occurs through an energy-investment phase in which phosphorylated intermediates are synthesized at the expense of ATP and an energy-generation phase in which ATP is produced by substrate-level phosphorylation. In the energy-investment phase, glucose is phosphorylated by hexokinase (found in most tissues) or glucokinase (a hexokinase found in liver cells and pancreatic β cells). Hexokinase has a high affinity (low Km) and a low maximal velocity (Vmax) for glucose and is inhibited by glucose 6-phosphate. Glucokinase has a high Km and a high Vmax for glucose. It is regulated indirectly by fructose 6-phosphate (inhibits) and glucose (activates) via glucokinase regulatory protein. Glucose 6-phosphate is isomerized to fructose 6phosphate, which is phosphorylated to fructose 1,6-bisphosphate by phosphofructokinase-1 (PFK-1). This enzyme is allosterically inhibited by ATP and citrate and activated by AMP. Fructose 2,6-bisphosphate, whose synthesis by bifunctional phosphofructokinase-2 (PFK-2) is increased in the liver by insulin and decreased by glucagon, is the most potent allosteric activator of PFK-1. A total of two ATP are used during this phase of glycolysis. Fructose 1,6-bisphosphate is cleaved to form two trioses that are further metabolized by the glycolytic pathway, forming pyruvate. During this phase, four ATP and two nicotinamide adenine dinucleotide (NADH) are produced per glucose molecule. The final step in pyruvate synthesis from phosphoenolpyruvate is catalyzed by pyruvate kinase (PK). This enzyme is allosterically activated by fructose 1,6-bisphosphate, and the hepatic isozyme is inhibited covalently by glucagon via the cAMP pathway. PK deficiency accounts for the majority of all inherited defects in glycolytic enzymes. Effects are restricted to RBC and present as mild-tosevere chronic, nonspherocytic hemolytic anemia. Glycolytic gene transcription is enhanced by insulin and glucose. In anaerobic glycolysis, NADH is reoxidized to NAD+ by the reduction of pyruvate to lactate via lactate dehydrogenase. This occurs in cells such as RBC that lack mitochondria and in tissues such as exercising muscle, where production of NADH exceeds the oxidative capacity of the respiratory chain. Elevated concentrations of lactate in the plasma (lactic acidosis) occur with circulatory system collapse or shock. Pyruvate also can be 1) oxidatively decarboxylated to acetyl CoA by pyruvate dehydrogenase, 2) carboxylated to oxaloacetate (a TCA cycle intermediate) by pyruvate carboxylase, or 3) reduced to ethanol by microbial pyruvate decarboxylase.
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