The Cori Cycle

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Transcript of The Cori Cycle

Once again I want to thank Larry Moran over at Sandwalk for these posts. I've collected them in one place so they aren't lost and that I can find them again when I would like to use them [non-profit, teaching only].

Part 1:The Cori CycleAnimals can synthesize glucose 6-phosphate via gluconeogenesis just like all other species. However, unlike most species, animals can convert glucose 6-phosphate to glucose, which is secreted into the circulatory system. Mammals, in particular, have a sophisticated cycle of secretion and uptake of glucose. It's called the Cori cycle after the Nobel Laureates: Carl Ferdinand Cori and Gerty Theresa Cori.

The glucose 6-phosphate molecules synthesized in the liver can either be converted to glycogen [Glycogen Synthesis] or converted to glucose and secreted into the blood stream. The glucose molecules are taken up by muscle cells where they can be stored as glucogen. During strenuous exercise the glycogen is broken down to glucose 6-phosphate [Glycogen Degradation] and oxdized via the glycolysis pathway. This pathway yields ATP that is used in muscle contraction. If oxygen is limiting, the end product of glucose breakdown isn't CO2 but lactate. Lactate is secreted into the blood stream where it is taken up by the liver and converted to pyruvate by the enzyme lactate dehydrogenase. Pyruvate is the substrate for gluconeogenesis. The synthesis of glucose in the liver requires energy in the form of ATP and this energy is supplied by a variety of sources. The breakdown of fatty acids is the source shown in the figure. The Cori cycle preserves carbon atoms. The six carbon molecule, glucose, is split into two 3-carbon molecules (lactate) that are then converted to another 3-carbon molecule (pyruvate). Two pyruvates are joined to make glucose. Part 2:

Glycogen SynthesisAll cells are capable of making glucose. The pathways is called gluconeogenesis and the end product is not actually glucose but a phosphorylated intermediate called glucose-6-phosphate. Glucose-6-phosphate (G6P) serves as the precursor for synthesis of many other compounds such as the ribose sugars needed in making DNA and RNA. The only organisms that make free glucose are multicellular organisms, such as animals, that secrete it into the circulatory system so it can be taken up and used by other cells (Glucose-6-phosphate cannot diffuse across the membrane so it's retained within cells.) In times of plenty, G6P may not be needed in further biosynthesis reactions so cells have evolved a way of storing, or banking, excess glucose. The stored glucose molecules can then be retrieved when times get tough. Think of bacteria growing in the ocean, for example. There may be times when an abundant supply of CO2 combined with a surplus of inorganic energy sources (e.g., H2S) allows for synthesis of lots of G6P. These cells can store the excess G6P by making glycogena polymer of glucose residues.

Glycogen consists of long chains of glucose molecules joined end-to-end through their carbon atoms at the 1 and 4 positions. The chains can have many branches. Completed chains can have up to 6000 glucose residues making glycogen one of the largest molecules in living cells. The advantage of converting G6P to glycogen is that it avoids the concentration effects of having too many small molecules floating around inside the cell. By compacting all these molecules into a single large polymer the cell is able to form large granules of stored sugar (see photo above). The first step in the synthesis of glycogen is the conversion of glucose-6-phosphate to glucose-1phosphate by the action of an enzyme called phosphoglucomutase. (Mutases are enzymes that rearrange functional groups, in this case moving a phosphate from the 6 position of glucose to the 1 position.) The glycogen synthesis reaction requires adding new molecules that will be connected to the chain through their #1 carbon atoms so this preliminary reaction is required in order to "activate" the right end of the glucose residue.

Glucose-1-phosphate is the "Cori ester" [Monday's Molecule #25] that was discovered by Carl Cori and Gerty Cori while they were working out this pathway [Nobel Laureates: Carl Cori and Gerty Cori]. The next step is the conversion of glucose-1-phosphate to the real activated sugar, UDP-glucose. The enzyme is UDP-glucose pyrophosphorylase and the UDP-glucose product is similar to many other compound that are activated by attaching a nucleotide. In some bacteria, the activated sugar is ADP-glucose but the enzyme is the same as that found in eukaryotes. ADP-glucose is the activated sugar in plants, as well. In plants the storage molecules are starch, not glycogen, but the difference is small (starch has fewer branches).

Glycogen synthesis is a polymerization reaction where glucose units in the form of UDP-glucose are added one at a time to a growing polysaccharide chain. The reaction is catalyzed by glycogen synthase.

[Laurence A. Moran. Some of the text is from Principles of Biochemistry 4th ed. Pearson/Prentice Hall]

Part 3:Glycogen Degradation/UtilizationGlucose is stored as the intracellular polysaccharides starch and glycogen. Starch occurs mostly in plants. Glycogen is an important storage polysaccharide in bacteria, protists, fungi and animals. Glycogen is stored in large granules. In mammals, these granules are found in muscle and liver cells. In electron micrographs, liver glycogen appears as clusters of cytosolic granules with a diameter of 100 nmmuch larger than ribosomes. The enzymes required for synthesis of glycogen are found in muscle and liver cells [Glycogen Synthesis]. Those same cells contain the enzymes for glycogen degradation. The glucose residues of starch and glycogen are released from storage polymers through the action of enzymes called polysaccharide phosphorylases: starch phosphorylase (in plants) and glycogen phosphorylase (in many other organisms). These enzymes catalyze the removal of glucose residues from the ends of starch or glycogen. As the name implies, the enzymes catalyze phosphorolysiscleavage of a bond by group transfer to an oxygen atom of phosphate. In contrast to hydrolysis (group transfer to water), phosphorolysis produces phosphate esters. Thus, the first product of polysaccharide breakdown is -D-glucose 1-phosphate, not free glucose.

Glucose 1-phosphate is one of the precursors required for glycogen synthesis. It is the "Cori ester" [Monday's Molecule] discovered by Carl Cori and Gerty Cori [Nobel Laureates: Carl Cori and Gerty Cori]. The Cori's also discovered and characterized glycogen phosphorylase. In order for glucose 1-phosphate to be used in other pathways it has to be converted to glucose 6phosphate by the enzyme phosphoglucomutase. This is the same enzyme that's used in the synthesis of glycogen from glucose 6-phosphate. Glucose 6-phosphate can be oxidzed by the glycolysis pathway to produce ATP. This is what happens in muscle cells. Glucose is stored as glycogen during times of rest but during exercise the glycogen is broken down to glucose 6phosphate and glycolysis is activated. The resulting ATP is used in muscle activity. Obviously, there has to be a balance between the synthesis and degradation of glycogen and this balance is maintained by regulating the activities of the biosynthesis and degradation enzymes. This regulation occurs at many levels. Regulation by hormones is one of the classic examples of a signal transduction pathway in mammals. [Laurence A. Moran. Some of the text is from Principles of Biochemistry 4th ed. Pearson/Prentice Hall]

Part 4:

Regulating Glycogen MetabolismMammalian glycogen stores glucose in times of plenty (after feeding, a time of high glucose levels) and supplies glucose in times of need (during fasting or in fight-or-flight situations). In muscle, glycogen provides fuel for muscle contraction. In contrast, liver glycogen is largely converted to glucose that exits liver cells and enters the bloodstream for transport to other tissues that require it [The Cori Cycle]. Both the mobilization and synthesis of glycogen are regulated by hormones. The regulation of glycogen metabolism is a good way to introduce the idea of signal transduction. This is a very popular part of modern biochemistry. It's basically a way in which signals from outside the cell are transduced through a chain of molecules to affect a particular biochemical reaction. In this case, we'll examine how the hormones glucagon, epinephrine, and insulin regulate glycogen synthesis and glycogen degradation.

Let's look at glycogen synthesis. Glycogen synthase is the enzyme responsible for adding UDP-glucose to a growing chain of glycogen. There are two forms of this enzyme. The inactive form is called glycogen synthase b and it is phosphorylated (P). The active form is called glycogen synthase a and it does not carry a phosphate group. The activity of glycogen synthase is controlled by covalent modification just like pyruvate dehydrogenase [Regulating Pyruvate Dehydrogenase]. The phosphorlation of enzymes is performed by kinases. In this case it's a very common cellular kinase called protein kinase A (PKA). The complete name of the enzyme is cyclic AMP-dependent protein kinase A because its activity is regulated by a messenger molecule known as cyclic AMP (cAMP). Cyclic AMP is made from ATP by the enzyme adenylyl cyclase and it is degraded by the action of an enzyme called phosphodiesterase When cAMP is present inside the cell it binds to protein kinase A and activates it so that it can phosphorylate glycogen synthase. This shuts down glycogen synthesis by deactivating the enzyme. The key to hormonal regulation is the effect of the hormones on the production of cAMP. This takes place on the cell surface when the hormone binds to a cell surface receptor molecule. Insulin, glucagon, and epinephrine are the principal hormones that