Question

25. Glucagon is a hormone released by the pancreas in response to low blood glucose levels. It can stimulate a pathway that regulates flux through glycolysis and gluconeogenesis. Explain the steps involved in this pathway (beginning with glucagon binding to its receptor) and explain exactly how flux through glycolysis and gluconeogenesis are regulated in response to glueagon

Answer 1

Glucagon binds to a G protein-coupled receptor called glucagon receptor located in the plasma membrane. When the G protein interacts with the receptor, it results in the replacement of the GDP molecule that was bound to the alpha subunit with a GTP molecule. This substitution results in the releasing of the alpha subunit from the beta and gamma subunits. The alpha subunit specifically activates the next enzyme in the cascade, adenylate cyclase. Adenylate cyclase manufactures cyclic adenosine monophosphate, which activates protein kinase A. This enzyme, in turn, activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase b, converting it into the active form called phosphorylase a. Phosphorylase a is the enzyme responsible for the release of glucose-1-phosphate from glycogen polymers. An example of the pathway would be when glucagon binds to a transmembrane protein. The transmembrane proteins interacts with G protein. G alpha separates from G beta and gamma and interacts with the transmembrane protein adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP binds to protein kinase A, and the complex phosphorylates phosphorylase kinase. Phosphorylated phosphorylase kinase phosphorylates phosphorylase. Phosphorylated phosphorylate clips glucose units from glycogen as glucose 1-phosphate. The coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose-2,6-bisphosphate. The enzyme protein kinase A that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose-2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose-2,6-bisphosphate by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon.Glucagon stimulation of PKA also inactivates the glycolytic enzyme pyruvate kinase in hepatocytes.