Although most of the reactions of glycolysis are freely reversible, three are markedly exergonic and are considered to be physiologically irreversible. These reactions, catalyzed by hexokinase (and glucokinase), phosphofructokinase, and pyruvate kinase, are the major sites of regulation of glycolysis. Phosphofructokinase is significantly inhibited at normal intracellular concentrations of ATP, this inhibition can be rapidly relieved by 5′ AMP that is formed as ADP begins to accumulate. It is due to a failure to rapidly convert ADP to ATP, signaling the need for an increased rate of glycolysis. Cells that are capable of gluconeogenesis (reversing the glycolytic pathway) have different enzymes that catalyze reactions to reverse these irreversible steps: glucose-6-phosphatase, fructose 1,6-bisphosphatase and, to reverse the reaction of pyruvate kinase, pyruvate carboxylase, and phosphoenolpyruvate carboxykinase. The reciprocal regulation of phosphofructokinase in glycolysis and fructose 1,6-bisphosphatase in gluconeogenesis is discussed in Chapter 19.
Fructose enters glycolysis by phosphorylation to fructose-1 phosphate, and bypasses the main regulatory steps, resulting in formation of more pyruvate and acetyl-CoA than is required for ATP formation. In addition, increases in fructose-1-P in the liver activate glucokinase (compete for binding of glucokinase with the glucokinase regulatory protein), amplifying hepatic glucose uptake and increasing hepatic lipogenesis and predisposing to hepatic steatosis.
In Erythrocytes, the First Site of ATP Formation in Glycolysis May Be Bypassed
In erythrocytes, the reaction catalyzed by phosphoglycerate kinase may be bypassed to some extent by the reaction of bisphosphoglycerate mutase, which catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate, followed by hydrolysis to 3-phosphoglycerate and Pi , catalyzed by 2,3-bisphosphoglycerate phosphatase(Figure 1). This path way involves no net yield of ATP from glycolysis, but provides 2,3-bisphosphoglycerate, which binds to hemoglobin, decreasing its affinity for oxygen. This increases the efficiency with which hemoglobin delivers oxygen to tissues .
Fig1. The 2,3-bisphosphoglycerate pathway in erythrocytes.
