-> 9 enzymes as in total amount of enzymes for glycolysis, glucogenesis, glycoge
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Question
-> 9 enzymes as in total amount of enzymes for glycolysis, glucogenesis, glycogen making as well as glycogen breaking. --> What enzyme phosphorylates and what enzyme dephosphorylates.
-->How would you explain the results of the blood test?
Explanation / Answer
Glycogen Structure-
Glycogen is a polymer of glucose (up to 120,000 glucose residues) and is a primary carbohydrate storage form in animals. The polymer is composed of units of glucose linked alpha(1-4) with branches occurring alpha(1-6) approximately every 8-12 residues. The end of the molecule containing a free carbon number one on glucose is called a reducing end. The other ends are all called non-reducing ends. Related polymers in plants include starch (alpha(1-4) polymers only) and amylopectin (alpha (1-6) branches every 24-30 residues).
Glycogen provides an additional source of glucose besides that produced via gluconeogenesis. Because glycogen contains so many glucoses, it acts like a battery backup for the body, providing a quick source of glucose when needed and providing a place to store excess glucose when glucose concentrations in the blood rise. The branching of glycogen is an important feature of the molecule metabolically as well. Since glycogen is broken down from the "ends" of the molecule, more branches translate to more ends, and more glucose that can be released at once. Liver and skeletal muscle are primary sites in the body where glycogen is found.
Overview
The primary advantages of storage carbohydrates in animals are that
1) energy is not released from fat (other major energy storage form in animals) as fast as from glycogen;
2) glycolysis provides a mechanism of anaerobic metabolism (important in muscle cells that cannot get oxygen as fast as needed); and
3) glycogen provides a means of maintaining glucose levels that cannot be provided by fat.
Breakdown of glycogen involves 1) release of glucose-1-phosphate (G1P), 2) rearranging the remaining glycogen (as necessary) to permit continued breakdown, and 3) conversion of G1P to G6P for further metabolism. Remember that G6P can be 1) broken down in glycolysis, 2) converted to glucose by gluconeogenesis, and 3) oxidized in the pentose phosphate pathway.
Glycogen Breakdown
Glycogen Phosphorylase catalyzes breakdown of glycogen into Glucose-1-Phosphate (G1P). The reaction that produces G1P from glycogen is a phosphorolysis, not a hydrolysis reaction. The distinction is that hydrolysis reactions use water to cleave bigger molecules into smaller ones, but phosphorolysis reactions instead use phosphate for the same purpose. Note that the phosphate is just that - it does NOT come from ATP. Since ATP is NOT used to put phosphate on G1P, the reaction saves the cell energy. In addition, the phosphate on the G1P helps prevent the molecule from leaving the cell as it is. Glycogen phosphorylase will only act on non-reducing ends of a glycogen chain that are at least 5 glucoses away from a branch point. A second enzyme, Glycogen Debranching Enzyme (GDE), is therefore needed to convert alpha(1-6) branches to alpha(1-4) branches.
Liver
As noted in the class previously, the liver is essential for monitoring and maintaining a relatively constant level of glucose in the bloodstream. Conditions leading to glucose concentrations being too high or too low are very detrimental. It was noted that the liver is involved in gluconeogenesis in the Cori cycle and it should come as no surprise that the liver is involved in glycogen breakdown and synthesis because these pathways allow the liver to remove glucose from the bloodstream for glycogen synthesis when blood glucose is high and to release glucose into the bloodstream from glycogen breakdown when blood glucose levels are too low. You may recall that the enzyme glucose-6-phosphatase (G6Pase) catalyzes the last step of gluconeogenesis - conversion of G6P to glucose + phosphate. This enzyme is necessary also for release of glucose into the bloodstream from glycogen metabolism (glycogen -> G1P -> G6P -> Glucose). It is interesting to note that G6Pase is ABSENT FROM MUSCLE. This is because muscle does NOT export glucose. the liver, on the other hand, DOES export glucose and thus has abundant supplies of the enzyme.
Mechanism of Glycogen Phosphorylase Action
Glycogen phosphorylase uses phosphate instead of water to break down glycogen. Glycogen phosphorylase manages to use phosphate to catalyze glycogen breakdown by employing the coenzyme pyridoxal phosphate (PLP). This coenzyme forms a Schiff base intermediate with a lysine residue of the enzyme (see HERE). The 5' phosphate of PLP act as a proton donor and then as a proton acceptor (acid-base catalyst). Orthophosphate acts to donate a proton to carbon 4 of the glycogen chain and simultaneously acquire a proton from PLP. The carbonium ion thus created is attacked by orthophosphate to form alpha-glucose-1-phosphate. The mechanism can be seen
Regulation of Glycogen Phosphorylase
In order to avoid a futile cycle of glycogen synthesis and breakdown simultaneously, cells have evolved an elaborate set of controls that ensure only one pathway is primarily active at a time. Regulation occurs on the enzymes glycogen phosphorylase and glycogen synthase, and involves allosterism, covalent modification of enzymes and, ultimately, hormonal control.
Muscle Glycogen Phosphorylase Regulation
In muscle, glycogen phosphorylase exists as a usually active form (I'll call GPa) and a usually inactive form (GPb). It is not readily apparent from the figure, but GPa and GPb differ chemically only in that GPa is phosphorylated (two phosphates), but GPb is not. GPb is converted to GPa by phosphorylation by an enzyme known as phosphorylase kinase.
Differences in Liver Glycogen Phosphorylase
Glycogen phosphorylase is very similar to, but not identical to the one found in muscle. Related enzymes like these are called isozymes, for the fact that they are different forms of the same enzyme. The subtle changes in liver glycogen phosphorylase cause GPa to have a property that muscle glycogen phosphorylase does not - namely that GPa is allosterically inhibited by the accumulation of glucose. Glucose binding to liver GPa causes it to convert into the T form.
Activation of Glycogen Phosphorylase
Because the relative amounts of GPa and GPb largely govern the overall process of glycogen breakdown, it is important to understand the controls on the enzymes that interconvert GPa and GPb. Interconversion of GPa and GPb is accomplished by the enzyme Phosphorylase Kinase, which transfers phosphates from 2 ATPs to GPb to form GPa. Phosphorylase kinase is present in a low activity form and a high activity form. The enzyme can be activated by two mechanisms
Overall Glycogen Breakdown Regulation
As noted above, phosphorylase kinase is activated by PKA. PKA is, of course, activated by cAMP, which is, in turn produced by adenlyate cyclase after activation by a G protein. G proteins are activated ultimately by binding of ligands to specific 7TM receptors. Common ligands for receptors include epinephrine (binds beta-adrenergic receptor) and glucagon (bind glucagon receptor). Epinephrine exerts it greatest effects on muscle and glucagon works preferentially on the liver.
Regulation of Glycogen Synthesis
The pattern of regulation of glycogen biosynthesis is similar to that of glycogen breakdown. It also has a cascading covalent modification system similar to the glycogen breakdown system described above. In fact, part of the system is identical to glycogen breakdown. Epinephrine or glucagon stimulates adenylate cyclase to make cAMP, which activates PKA, which activates phosphorylase kinase. As you should recall, this is the same as for glycogen breakdown. In glycogen breakdown, phosphorylase kinase phosphorylates GPb to the more active form, GPa. In glycogen synthesis, phosphorylase kinase phosphorylates the active form of Glycogen Synthase (GSa), and converts it into the usually inactive b form (called GSb). Note the conventions for glycogen synthase and glycogen phosphorylase. For both enzymes, the more active forms are called the 'a' forms (GPa and GSa) and the less active forms are called the 'b' forms (GPb and GSb). One MAJOR difference, however, is that GPa has a phosphate, but GSa does not and GPb has no phosphate, but GSb does. Thus phosphorylation and dephosphorylation have OPPOSITE EFFECTS on the enzymes of glycogen metabolism.
Maintaining Blood Glucose Levels
After a meal, blood glucose levels rise and glycogen synthesis in the liver is stimulated. GPa in the liver rises and falls with changing blood glucose levels. It turns out that GPa acts as a glucose sensor in the liver. Remember that binding of glucose to GPa in the liver converts it from the R to the T state (inactive). This conformational change also enhances the ability of PP to dephosphorylate GPa, converting it to the GPb form. Interestingly, PP binds GPa tightly normally, but is only active when GPa is in the T state.
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