Tca

FIGURE 3 Biochemical pathways of glucose metabolism in hepatocytes. Reactions that are accelerated in the presence of glucagon are shown in blue.

many minutes or even hours are needed to change the amount of an enzyme.

Glycogenolysis

Cyclic AMP formed in response to the interaction of glucagon with its G-protein-coupled receptors on the surface of hepatocytes activates protein kinase A, which catalyzes phosphorylation, and hence activation, of an enzyme called phosphorylase kinase (Fig. 4). This enzyme, in turn, catalyzes phosphorylation of another enzyme, glycogen phosphorylase, which cleaves glycogen stepwise to release glucose-1-phosphate. Glucose-1-phosphate is the substrate for glycogen synthase, which catalyzes the incorporation of glucose into glycogen. Glycogen synthase is also a substrate for protein kinase A and is inactivated when phosphorylated. Thus by increasing the formation of cyclic AMP, glucagon

41. The Pancreatic Islets

Phosphorylase kinase (inactive)

Protein Kinase A

Phosphorylase (inactive)

phosphorylase-P (active)

Phosphorylase kinase (inactive)

Protein Kinase A

Phosphorylase (inactive)

phosphorylase-P (active)

glycogen synthase-P (inactive)

glycogen synthase (active)

glucose-1-P

FIGURE 4 Role of protein kinase A (cyclic AMP-dependent protein kinase) in glycogen metabolism.

glycogen synthase-P (inactive)

glycogen synthase (active)

glucose-1-P

FIGURE 4 Role of protein kinase A (cyclic AMP-dependent protein kinase) in glycogen metabolism.

simultaneously promotes glycogen breakdown and prevents recycling of glucose to glycogen. Cyclic AMP-dependent phosphorylation of enzymes that regulate the glycolytic pathway at the level of phosphofructoki-nase and acetyl coenzyme A (CoA) carboxylase (see later discussion) prevents consumption of glucose-6-phos-phate by the hepatocyte itself, leaving dephosphorylation and diffusion into the blood as the only pathway open to newly depolymerized glucose.

Gluconeogenesis

Precursors of glucose enter the gluconeogenic pathway as 3- or 4-carbon compounds. Glucagon directs their conversion to glucose by accelerating their condensation to fructose phosphate while simultaneously blocking their escape from the gluconeogenic pathway (cycles III and IV in Fig. 3). Cyclic AMP controls production of a potent allosteric regulator of metabolism called fructose-2,6-bisphosphate. This compound, when present even in tiny amounts, activates phosphofructokinase and inhibits fructose-1,6-bisphosphatase, thereby directing flow of substrate toward glucose breakdown rather than glucose formation (Fig. 5). Fructose-2,6-bisphosphate, which should not be confused with fructose-1,6-bisphosphate, is formed from fructose-6-phosphate by the action of an unusual bifunctional enzyme that catalyzes either phosphorylation offructose-6-phosphate to fructose-2,6-bisphosphate or dephosphorylation of fructose-2,6-bisphosphate to fructose-6-phosphate, depending on its own state of phosphorylation. This enzyme is a substrate for protein kinase A and behaves as a phosphatase when it is phosphorylated. Its activity in the presence of cyclic AMP rapidly depletes the hepatocyte of fructose-2,6-bisphosphate, and substrate therefore flows toward glucose production.

The other important regulatory step in gluconeogen-esis is phosphorylation and dephosphorylation of pyru-vate (cycle IV in Fig. 3). It is here that the 3- and 4-carbon fragments enter or escape from the gluconeo-genic pathway. The cytosolic enzyme that catalyzes dephosphorylation of phosphoenol pyruvate (PEP) was inappropriately named pyruvate kinase before it was recognized that direct phosphorylation of pyruvate does not occur under physiologic conditions and that this enzyme acts only in the direction of dephosphorylation (Fig. 6). Regulation of this enzyme is complex. Pyruvate kinase is another substrate for protein kinase A and is powerfully inhibited when phosphorylated, but the inhibition can be overcome by fructose-1,6-bisphosphate. Thus, activation of protein kinase A has the duel effect of decreasing pyruvate kinase activity directly and of decreasing the abundance of its activator, fructose-1,6-bisphosphate, by reactions shown in Fig. 5. Inhibiting pyruvate kinase may be the single most important effect of glucagon on the gluconeogenic pathway. On a longer time scale, glucagon inhibits the synthesis of pyruvate kinase. Phosphorylation of pyruvate requires a complex series of reactions in which pyruvate must first enter mitochondria where it is carboxylated to form oxaloacetate. Entry of pyruvate across the mitochon-drial membrane is accelerated by glucagon, but the mechanism for this effect is not known. Oxaloacetate is converted to cytosolic PEP by the catalytic activity of PEP carboxykinase. Synthesis of this enzyme is

Protein Kinase A

fructose -6- P

Protein Kinase A

fructose -6- P

fructose-1,6-bisP phosphatase fructose -1,6-bisP

FIGURE 5 Regulation of fructose-1,6-bisphosphate metabolism by protein kinase A (cyclic AMP-dependent protein kinase) and fructose-2,6-bisphosphate. Fructose-2,6-bisphosphate, whose formation depends on protein kinase A, activates ( + ) phosphofructokinase and inhibits (—) fructose-1,6-bisphosphatase.

fructose-1,6-bisP phosphatase cytosol triosephosphate

Protein Kinase A

PEP carboxy kinase oxaloacetate

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Get Rid of Gallstones Naturally

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