Question

8. a. Which steps and enzymes are targets of regulation in the metabolism and catabolism of glucose through glycolysis and gluconeogenesis?

Be sure to include what molecules are utilized in regulation and their potential effects in each pathway.

For the following scenarios, please explain in detail the effect on both glycolysis and gluconeogenesis, as well as the effects on any of the enzymes.

b. The cellular concentration of ATP increases

c. The cellular concentration of ATP decreases

d. The body has high blood sugar

e. The body has low blood sugar

Answer 1

(a). While most steps in gluconeogenesis are the reverse of those found in glycolysis, three regulated and strongly endergonic reactions are replaced with more kinetically favorable reactions. Hexokinase, phosphofructokinase, and pyruvate kinase enzymes of glycolysis are replaced with glucose-6-phosphatase, fructose-1,6-bisphosphatase, and PEP carboxykinase/pyruvate carboxylase. These enzymes are typically regulated by similar molecules, but with opposite results. For example, acetyl CoA and citrate activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively), while at the same time inhibiting the glycolytic enzyme pyruvate kinase. This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevents a futile cycle of synthesizing glucose to only break it down

(b and c.) AMP stimulates phosphofructokinase, whereas ATP and citrate inhibit it. Fructose 1,6-bisphosphatase, on the other hand, is inhibited by AMP and activated by citrate. A high level of AMP indicates that the energy charge is low and signals the need for ATP generation. Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are abundant. Under these conditions, glycolysis is nearly switched off and gluconeogenesis is promoted.

(d and e).In hepatocytes, glycolysis is involved in the control of hepatic glucose production. The latter, when excessive, contributes to hyperglycemia in diabetes. In pancreatic β cells, glycolysis couples glucose-stimulated insulin secretion. Absolute or relatively low levels of circulating insulin causes hyperglycemia. In adipocytes, glycolysis generates metabolites for lipogenesis and channels fatty acids from excessive oxidation to triglyceride synthesis, thereby reducing oxidative stress. With increased proinflammatory status, adipocytes produce pro-hyperglycemic factors and bring about hyperglycemia and insulin resistance. In hypothalamic neurons, glycolysis conveys nutrient sensing that is related to feeding control. Dysregulation of glycolysis occurs in conditions of insulin deficiency or resistance, and is attributable to inappropriate amount and/or activities of metabolic and regulatory enzymes of glycolysis. Targeting key metabolic and regulatory enzymes to enhance glycolysis may offer viable approaches for treatment of diabetes