The interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate is stringently controlled Figure As discussed in Section Fructose 1,6-bisphosphatase, on the other hand, is inhibited by AMP and activated by citrate. Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are abundant.
Under these conditions, glycolysis is nearly switched off and gluconeogenesis is promoted. Reciprocal Regulation of Gluconeogenesis and Glycolysis in the Liver. The level of fructose 2,6-bisphosphate is high in the fed state and low in starvation.
Another important control is the inhibition of pyruvate kinase by phosphorylation during starvation. Phosphofructokinase and fructose 1,6-bisphosphatase are also reciprocally controlled by fructose 2,6-bisphosphate in the liver Section The level of F-2,6-BP is low during starvation and high in the fed state, because of the antagonistic effects of glucagon and insulin on the production and degradation of this signal molecule.
Fructose 2,6-bisphosphate strongly stimulates phosphofructokinase and inhibits fructose 1,6-bisphosphatase. Hence, glycolysis is accelerated and gluconeogenesis is diminished in the fed state. During starvation, gluconeogenesis predominates because the level of F-2,6-BP is very low. Glucose formed by the liver under these conditions is essential for the viability of brain and muscle. The interconversion of phosphoenolpyruvate and pyruvate also is precisely regulated.
Recall that pyruvate kinase is controlled by allosteric effectors and by phosphorylation Section High levels of ATP and alanine, which signal that the energy charge is high and that building blocks are abundant, inhibit the enzyme in liver.
Conversely, pyruvate carboxylase, which catalyzes the first step in gluconeogenesis from pyruvate, is activated by acetyl CoA and inhibited by ADP.
Likewise, ADP inhibits phosphoenolpyruvate carboxykinase. Hence, gluconeogenesis is favored when the cell is rich in biosynthetic precursors and ATP. The amounts and the activities of these essential enzymes also are regulated. The regulators in this case are hormones. Hormones affect gene expression primarily by changing the rate of transcription, as well as by regulating the degradation of mRNA. Insulin, which rises subsequent to eating, stimulates the expression of phosphofructokinase, pyruvate kinase, and the bifunctional enzyme that makes and degrades F-2,6-BP.
Glucagon, which rises during starvation, inhibits the expression of these enzymes and stimulates instead the production of two key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and fructose 1,6-bisphosphatase.
Transcriptional control in eukaryotes is much slower than allosteric control; it takes hours or days in contrast with seconds to minutes. The richness and complexity of hormonal control are graphically displayed by the promoter of the phosphoenolpyruvate carboxykinase gene, which contains regulatory sequences that respond to insulin, glucagon, glucocorticoids, and thyroid hormone Figure The Promoter of the Phosphoenolpyruvate Carboxykinase Gene.
This promoter is approximately bp in length and contains regulatory sequences response elements that mediate the action of several hormones. A pair of reactions such as the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate and its hydrolysis back to fructose 6-phosphate is called a substrate cycle. As already mentioned, both reactions are not simultaneously fully active in most cells, because of reciprocal allosteric controls. However, the results of isotope-labeling studies have shown that some fructose 6-phosphate is phosphorylated to fructose 1,6-bisphosphate in gluconeogenesis.
There also is a limited degree of cycling in other pairs of opposed irreversible reactions. This cycling was regarded as an imperfection in metabolic control, and so substrate cycles have sometimes been called futile cycles. Indeed, there are pathological conditions, such as malignant hyperthermia, in which control is lost and both pathways proceed rapidly with the concomitant generation of heat by the rapid, uncontrolled hydrolysis of ATP.
Despite such extraordinary circumstances, it now seems likely that substrate cycles are biologically important. One possibility is that substrate cycles amplify metabolic signals. Suppose that the rate of conversion of A into B is and of B into A is 90, giving an initial net flux of The starting substance or the reactant in glycolysis is Glucose.
It undergoes a series of steps to form the end product, the Pyruvate. Picture 2: The process of Glycolysis Image source : upload. The process of glycolysis involves a series of steps starting with glucose as the reactant.
The first step is important and one of the three irreversible steps in the process. In the presence of the enzyme hexokinase, glucose takes up a phosphate group from the ATP and forms GlucosePhosphate.
Apart from glycolysis, this compound is the gateway to many other important processes like glycogen and lipid synthesis. In the next step, there is no new compound synthesis but just rearrangement of the atoms isomerisation to form fructosephosphate from glucosephosphate and this step is catalysed by enzyme phosphohexose isomerise. The next step is the second irreversible step in the process and the one which is more important in the regulation of glycolysis.
Fructose 6 phosphate is phosphorylated by ATP to Fructose-1,6 bisphosphate in presence of phosphofructokinase 1. The Fructose-1,6-bisphosphate is a 6 carbon compound same as that of glucose. In this step, it is cleaved to two different compounds — Glyceradehydephosphate and dihydroxyacetone phosphate by the enzyme aldolase. Both are 3 carbon compounds which are interchangeable to each other. From the next step, consider that 2 molecules of Glyceraldehydephosphate are undergoing the process simultaneously.
The Glyceraldehydephosphate G3P is phosphorylated to 1,3 bisphosphoglycerate 1,3 BPG by inorganic phosphate by the enzyme glyceraldehydephosphate dehydrogenase. This reaction is NAD mediated. Thus 2 ATP molecules are generated in this step considering that 2 molecules of G3P are undergoing glycolysis simultaneously. The 3-phosphoglycerate is converted to phosphoenolpyruvate PEP by enolase.
The end product is Pyruvate. This is the last step in aerobic glycolysis which is irreversible and yields 2 ATP molecules. Glucose 6-phosphate can also be converted into glycogen or it can be oxidized by the pentose phosphate pathway Section The first irreversible reaction unique to the glycolytic pathway, the committed step , Section Thus, it is highly appropriate for phosphofructokinase to be the primary control site in glycolysis.
In general, the enzyme catalyzing the committed step in a metabolic sequence is the most important control element in the pathway. Pyruvate kinase, the enzyme catalyzing the third irreversible step in glycolysis, controls the outflow from this pathway. This final step yields ATP and pyruvate, a central metabolic intermediate that can be oxidized further or used as a building block. Several isozymic forms of pyruvate kinase a tetramer of kd subunits encoded by different genes are present in mammals: the L type predominates in liver, and the M type in muscle and brain.
The L and M forms of pyruvate kinase have many properties in common. Both bind phosphoenolpyruvate cooperatively. Fructose 1,6-bisphosphate, the product of the preceding irreversible step in glycolysis, activates both isozymes to enable them to keep pace with the oncoming high flux of intermediates. ATP allosterically inhibits both the L and the M forms of pyruvate kinase to slow glycolysis when the energy charge is high. Finally, alanine synthesized in one step from pyruvate, Section The isozymic forms differ in their susceptibility to covalent modification.
The catalytic properties of the L form—but not of the M form—are also controlled by reversible phosphorylation Figure When the blood-glucose level is low, the glucagon-triggered cyclic AMP cascade Section These hormone - triggered phosphorylations , like that of the bifunctional enzyme controlling the levels of fructose 2,6- bisphosphate , prevent the liver from consuming glucose when it is more urgently needed by brain and muscle Section We see here a clear-cut example of how isoenzymes contribute to the metabolic diversity of different organs.
We will return to the control of glycolysis after considering gluconeogenesis. Control of the Catalytic Activity of Pyruvate Kinase.
Pyruvate kinase is regulated by allosteric effectors and covalent modification. Several glucose transporters mediate the thermodynamically downhill movement of glucose across the plasma membranes of animal cells. The common structural theme is the presence of 12 transmembrane segments Figure Model of a Mammalian Glucose Transporter. Muekler, C. Caruso, S.
Baldwin, M. Panico, M. Blench, H. Morris, W. Allard, G. Lienhard, and H. Their K M value for glucose is about 1 mM, significantly less than the normal serum-glucose level, which typically ranges from 4 mM to 8 mM. Hence, glucose enters these tissues at a biologically significant rate only when there is much glucose in the blood.
The pancreas can thereby sense the glucose level and accordingly adjust the rate of insulin secretion. Insulin signals the need to remove glucose from the blood for storage as glycogen or conversion into fat Section The presence of insulin, which signals the fed state, leads to a rapid increase in the number of GLUT4 transporters in the plasma membrane.
Hence, insulin promotes the uptake of glucose by muscle and fat. The amount of this transporter present in muscle membranes increases in response to endurance exercise training.
GLUT5, present in the small intestine, functions primarily as a fructose transporter. This family of transporters vividly illustrates how isoforms of a single protein can significantly shape the metabolic character of cells and contribute to their diversity and functional specialization.
The transporters are members of a superfamily of transporters called the major facilitator MF superfamily. Members of this family transport sugars in organisms as diverse as E.
An elegant solution to the problem of fuel transport evolved early and has been tailored to meet the needs of different organisms and even different tissues. It has been known for decades that tumors display enhanced rates of glucose uptake and glycolysis. We now know that these enhanced rates of glucose processing are not fundamental to the development of cancer, but we can ask what selective advantage they might confer on cancer cells.
Cancer cells grow more rapidly than the blood vessels to nourish them; thus, as solid tumors grow, they are unable to obtain oxygen efficiently. In other words, they begin to experience hypoxia. Under these conditions, glycolysis leading to lactic acid fermentation becomes the primary source of ATP.
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