Whether the bifunctional protein is phosphorylated or not is regulated in large measure by PKA and protein phosphatase activity see Ref. When glucose is abundant, glycolysis tends to be more active. If levels of fructose 6-phosphate increase, phosphoprotein phosphatase activity is stimulated this feedforward stimulation is indicated in Ref. The protein phosphatase may also be stimulated in cells responsive to insulin signaling.
When glucose is scarce, PKA will be activated in cells responsive to glucagon , which favors FBPase2 activity, lowering levels of fructose 2,6-bisphosphate. The loss of the PFK activation by the latter slows down glycolysis.
In liver, the effect of glucagon is also to stimulate glycogen breakdown, thus making the glucose stored therein available for maintenance of blood-glucose homeostasis. The other points at which the flux through the glycolytic pathway can be controlled include the activities of hexokinase and pyruvate kinase. Hexokinase is subject to product inhibition by glucose 6-phosphate.
When PFK is less active, the rise in relative concentration of fructose 6-phosphate is soon reflected in a rise in glucose 6-phosphate levels. This also slows the rate of catalysis by hexokinase. In the liver, this mode of regulation can be bypassed as glucose 6-phosphate levels rise by the enzyme glucokinase.
Glucokinase is not inhibited by G6P, but its K M for glucose is significantly higher. Regulation of pyruvate kinase occurs via allosteric effects, and through different isozymic forms that differ in their capacity for regulation by covalent modification again, phosphorylation. In general, fructose 1,6-bisphosphate, the product of the PFK reaction, is an allosteric activator of pyruvate kinase, while ATP and alanine the latter signifies the abundance of pyruvate are allosteric inhibitors.
The L isozyme of pyruvate kinase is directly regulated by phosphorylation. The L form is expressed in the liver, and it is a substrate of PKA When blood glucose is low, glucagon stimulates a membrane associated adenylate cyclase, activating PKA, as explained above.
This leads to the phosphorylation of the L form of pyruvate kinase, which inhibits its activity. This makes metabolic sense, since when blood glucose is low, further consumption of glucose by glycolysis in the liver ought to be slowed down.
The fate of glucose 6-phosphate G6P is not determined solely by the rate of glycolysis. It is also utilized in the pentose phosphate pathway , or it can be directed toward "short-term storage" in the form of glycogen. Thus, when energy is required, glycolysis is activated. When energy is plentiful, the reaction is slowed down.
Finally, phosphofructokinase is inhibited by citrate. A large number of compounds—for example, fatty acids and amino acids—can be metabolized to TCA cycle intermediates. High concentrations of citrate indicate a plentiful supply of intermediates for energy production; therefore, high activity of the glycolytic pathway is not required. Fatty acids also allosterically inhibit pyruvate kinase, serving as an indicator that alternative energy sources are available for the cell.
This glycolytic intermediate is controlled by its own enzyme system. If glycolysis is activated, then the activity of pyruvate kinase must also be increased in order to allow overall carbon flow through the pathway. Physiologically, glycolysis produces energy at a high rate but for a short duration. Biopsies of animal muscle indicate two types of tissue; the two types have different metabolic activities.
The flight muscles in the breasts of chickens and turkeys, for example, are light, while the leg and other muscles are dark. In these tissues, metabolism of glucose is largely aerobic. Because only two ATP molecules are produced per glucose consumed by glycolysis, a limited amount of energy is available for muscle activity.
The muscle acts quickly, but for only a short time. Athletes' muscle composition reflects their relative sports. Step 1. The first step in glycolysis Figure 9. Hexokinase phosphorylates glucose using ATP as the source of the phosphate, producing glucosephosphate, a more reactive form of glucose. This reaction prevents the phosphorylated glucose molecule from continuing to interact with the GLUT proteins, and it can no longer leave the cell because the negatively charged phosphate will not allow it to cross the hydrophobic interior of the plasma membrane.
Step 2. In the second step of glycolysis, an isomerase converts glucosephosphate into one of its isomers, fructosephosphate. An isomerase is an enzyme that catalyzes the conversion of a molecule into one of its isomers. This change from phosphoglucose to phosphofructose allows the eventual split of the sugar into two three-carbon molecules. Step 3. The third step is the phosphorylation of fructosephosphate, catalyzed by the enzyme phosphofructokinase.
A second ATP molecule donates a high-energy phosphate to fructosephosphate, producing fructose-1,6- bi sphosphate. In this pathway, phosphofructokinase is a rate-limiting enzyme. This is a type of end product inhibition, since ATP is the end product of glucose catabolism. Step 4. The newly added high-energy phosphates further destabilize fructose-1,6-bisphosphate. The fourth step in glycolysis employs an enzyme, aldolase, to cleave 1,6-bisphosphate into two three-carbon isomers: dihydroxyacetone-phosphate and glyceraldehydephosphate.
Step 5. In the fifth step, an isomerase transforms the dihydroxyacetone-phosphate into its isomer, glyceraldehydephosphate. Thus, the pathway will continue with two molecules of a single isomer.
At this point in the pathway, there is a net investment of energy from two ATP molecules in the breakdown of one glucose molecule.
So far, glycolysis has cost the cell two ATP molecules and produced two small, three-carbon sugar molecules. Both of these molecules will proceed through the second half of the pathway, and sufficient energy will be extracted to pay back the two ATP molecules used as an initial investment and produce a profit for the cell of two additional ATP molecules and two even higher-energy NADH molecules.
Step 6. The sixth step in glycolysis Figure 9. The sugar is then phosphorylated by the addition of a second phosphate group, producing 1,3-bisphosphoglycerate. Note that the second phosphate group does not require another ATP molecule. Here again is a potential limiting factor for this pathway. If oxygen is available in the system, the NADH will be oxidized readily, though indirectly, and the high-energy electrons from the hydrogen released in this process will be used to produce ATP.
Step 7. In the seventh step, catalyzed by phosphoglycerate kinase an enzyme named for the reverse reaction , 1,3-bisphosphoglycerate donates a high-energy phosphate to ADP, forming one molecule of ATP. This is an example of substrate-level phosphorylation. A carbonyl group on the 1,3-bisphosphoglycerate is oxidized to a carboxyl group, and 3-phosphoglycerate is formed.
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