Atp

Fructose-6-phosphate

Glycolysis

Figure 67-3

Interconversions of the three major monosaccharides—glucose, fructose, and galactose—in liver cells.

and phosphate, and the glucose can then be transported through the liver cell membrane back into the blood.

Once again, it should be emphasized that usually more than 95 per cent of all the monosaccharides that circulate in the blood are the final conversion product, glucose.

Transport of Glucose Through the Cell Membrane

Before glucose can be used by the body's tissue cells, it must be transported through the tissue cell membrane into the cellular cytoplasm. However, glucose cannot easily diffuse through the pores of the cell membrane because the maximum molecular weight of particles that can diffuse readily is about 100, and glucose has a molecular weight of 180. Yet glucose does pass to the interior of the cells with a reasonable degree of freedom by the mechanism of facilitated diffusion. The principles of this type of transport are discussed in Chapter 4. Basically, they are the following. Penetrating through the lipid matrix of the cell membrane are large numbers of protein carrier molecules that can bind with glucose. In this bound form, the glucose can be transported by the carrier from one side of the membrane to the other side and then released. Therefore, if the concentration of glucose is greater on one side of the membrane than on the other side, more glucose will be transported from the high-concentration area to the low-concentration area than in the opposite direction.

The transport of glucose through the membranes of most tissue cells is quite different from that which occurs through the gastrointestinal membrane or through the epithelium of the renal tubules. In both these cases, the glucose is transported by the mechanism of active sodium-glucose co-transport, in which active transport of sodium provides energy for absorbing glucose against a concentration difference. This sodium co-transport mechanism functions only in certain special epithelial cells that are specifically adapted for active absorption of glucose. At other cell membranes, glucose is transported only from higher concentration toward lower concentration by facilitated diffusion, made possible by the special binding properties of membrane glucose carrier protein. The details of facilitated diffusion for cell membrane transport are presented in Chapter 4.

Insulin Increases Facilitated Diffusion of Glucose

The rate of glucose transport as well as transport of some other monosaccharides is greatly increased by insulin. When large amounts of insulin are secreted by the pancreas, the rate of glucose transport into most cells increases to 10 or more times the rate of transport when no insulin is secreted. Conversely, the amounts of glucose that can diffuse to the insides of most cells of the body in the absence of insulin, with the exception of liver and brain cells, are far too little to supply the amount of glucose normally required for energy metabolism.

In effect, the rate of carbohydrate utilization by most cells is controlled by the rate of insulin secretion from the pancreas. The functions of insulin and its control of carbohydrate metabolism are discussed in detail in Chapter 78.

Phosphorylation of Glucose

Immediately on entry into the cells, glucose combines with a phosphate radical in accordance with the following reaction:

Glucose —6-> Glucose-6-phosphate

This phosphorylation is promoted mainly by the enzyme glucokinase in the liver and by hexokinase in most other cells. The phosphorylation of glucose is almost completely irreversible except in the liver cells, the renal tubular epithelial cells, and the intestinal epithelial cells; in these cells, another enzyme, glucose phosphatase, is also available, and when this is activated, it can reverse the reaction. In most tissues of the body, phosphorylation serves to capture the glucose in the cell. That is, because of its almost instantaneous binding with phosphate, the glucose will not diffuse back out, except from those special cells, especially liver cells, that have phosphatase.

Glycogen Is Stored in Liver and Muscle

After absorption into a cell, glucose can be used immediately for release of energy to the cell, or it can be stored in the form of glycogen, which is a large polymer of glucose.

All cells of the body are capable of storing at least some glycogen, but certain cells can store large amounts, especially liver cells, which can store up to 5 to 8 per cent of their weight as glycogen, and muscle cells, which can store up to 1 to 3 per cent glycogen. The glycogen molecules can be polymerized to almost any molecular weight, with the average molecular weight being 5 million or greater; most of the glycogen precipitates in the form of solid granules.

This conversion of the monosaccharides into a high-molecular-weight precipitated compound (glycogen) makes it possible to store large quantities of carbohydrates without significantly altering the osmotic pressure of the intracellular fluids. High concentrations of low-molecular-weight soluble monosaccharides would play havoc with the osmotic relations between intracel-lular and extracellular fluids.

Glycogenesis—The Process of Glycogen Formation

The chemical reactions for glycogenesis are shown in Figure 67-4. From this figure, it can be seen that glucose-6-phosphate can become glucose-1-phosphate; this is converted to uridine diphosphate glucose, which is finally converted into glycogen. Several specific enzymes are required to cause these conversions, and any monosaccharide that can be converted into glucose can enter into the reactions. Certain smaller compounds, including lactic acid, glycerol, pyruvic acid, and some deaminated amino acids, can also be converted into glucose or closely allied compounds and then converted into glycogen.

Blood glucose

Cell membrane _

Glycogen

Uridine diphosphate glucose (Phosphorylase)

Glucose-1-phosphate

(glucokinase) | f Glucose

Glucose-6-phosphate

(phosphatase)

Glycolysis

Figure 67-4

Chemical reactions of glycogenesis and glycogenolysis, showing also interconversions between blood glucose and liver glycogen. (The phosphatase required for the release of glucose from the cell is present in liver cells but not in most other cells.)

Removal of Stored Glycogen— Glycogenolysis

Glycogenolysis means the breakdown of the cell's stored glycogen to re-form glucose in the cells. The glucose can then be used to provide energy. Glycogenol-ysis does not occur by reversal of the same chemical reactions that form glycogen; instead, each succeeding glucose molecule on each branch of the glycogen polymer is split away by phosphorylation, catalyzed by the enzyme phosphorylase.

Under resting conditions, the phosphorylase is in an inactive form, so that glycogen will remain stored.When it is necessary to re-form glucose from glycogen, the phosphorylase must first be activated. This can be accomplished in several ways, including the following two.

Activation of Phosphorylase by Epinephrine or by Glucagon. Two hormones, epinephrine and glucagon, can activate phos-phorylase and thereby cause rapid glycogenolysis. The initial effect of each of these hormones is to promote the formation of cyclic AMP in the cells, which then initiates a cascade of chemical reactions that activates the phosphorylase. This is discussed in detail in Chapter 78.

Epinephrine is released by the adrenal medullae when the sympathetic nervous system is stimulated. Therefore, one of the functions of the sympathetic nervous system is to increase the availability of glucose for rapid energy metabolism. This function of epineph-rine occurs markedly in both liver cells and muscle, thereby contributing, along with other effects of sympathetic stimulation, to preparing the body for action, as discussed fully in Chapter 60.

Glucagon is a hormone secreted by the alpha cells of the pancreas when the blood glucose concentration falls too low. It stimulates formation of cyclic AMP mainly in the liver cells, and this in turn promotes conversion of liver glycogen into glucose and its release into the blood, thereby elevating the blood glucose concentration. The function of glucagon in blood glucose regulation is discussed more fully in Chapter 78.

Release of Energy from the Glucose Molecule by the Glycolytic Pathway

Because complete oxidation of 1 gram-molecule of glucose releases 686,000 calories of energy and only 12,000 calories of energy are required to form 1 gram-molecule of ATP, energy would be wasted if glucose were decomposed all at once into water and carbon dioxide while forming only a single ATP molecule. Fortunately, all cells of the body contain special protein enzymes that cause the glucose molecule to split a little at a time in many successive steps, so that its energy is released in small packets to form one molecule of ATP at a time, forming a total of 38 moles of ATP for each mole of glucose metabolized by the cells.

The next sections describe the basic principles of the processes by which the glucose molecule is progressively dissected and its energy released to form ATP.

Glycolysis and the Formation of Pyruvic Acid

By far the most important means of releasing energy from the glucose molecule is initiated by glycolysis. The end products of glycolysis are then oxidized to provide energy. Glycolysis means splitting of the glucose molecule to form two molecules of pyruvic acid.

Glycolysis occurs by 10 successive chemical reactions, shown in Figure 67-5. Each step is catalyzed by at least one specific protein enzyme. Note that glucose is first converted into fructose-1,6-diphosphate and then split into two three-carbon-atom molecules, glyceraldehyde-3-phosphate, each of which is then converted through five additional steps into pyruvic acid.

Formation of ATP During Glycolysis. Despite the many chemical reactions in the glycolytic series, only a small portion of the free energy in the glucose molecule is released at most steps. However, between the 1,3-diphosphoglyceric acid and the 3-phosphoglyceric acid stages, and again between the phosphoenolpyruvic acid and the pyruvic acid stages, the packets of energy released are greater than 12,000 calories per mole, the amount required to form ATP, and the reactions are coupled in such a way that ATP is formed. Thus, a total of 4 moles of ATP were formed for each mole of fruc-tose-1,6-diphosphate that is split into pyruvic acid.

Yet 2 moles of ATP were required to phosphorylate the original glucose to form fructose-1,6-diphosphate before glycolysis could begin. Therefore, the net gain in

ATP molecules by the entire glycolytic process is only 2 moles for each mole of glucose utilized. This amounts to 24,000 calories of energy that becomes transferred to ATP, but during glycolysis, a total of 56,000 calories of energy were lost from the original glucose, giving an overall efficiency for ATP formation of only 43 per cent. The remaining 57 per cent of the energy is lost in the form of heat.

Conversion of Pyruvic Acid to Acetyl Coenzyme A

The next stage in the degradation of glucose is a two-step conversion of the two pyruvic acid molecules from Figure 67-5 into two molecules of acetyl coenzyme A (acetyl-CoA), in accordance with the following reaction:

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Essentials of Human Physiology

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