Guyton and Hall Textbook of Medical Physiology, 12th Ed


Protein Metabolism

imageAbout three quarters of the body solids are proteins. These include structural proteins, enzymes, nucleoproteins, proteins that transport oxygen, proteins of the muscle that cause muscle contraction, and many other types that perform specific intracellular and extracellular functions throughout the body.

The basic chemical properties that explain proteins’ diverse functions are so extensive that they constitute a major portion of the entire discipline of biochemistry. For this reason, the current discussion is confined to a few specific aspects of protein metabolism that are important as background for other discussions in this text.

Basic Properties

Amino Acids

The principal constituents of proteins are amino acids, 20 of which are present in the body proteins in significant quantities. Figure 69-1 shows the chemical formulas of these 20 amino acids, demonstrating that they all have two features in common: each amino acid has an acidic group (—COOH) and a nitrogen atom attached to the molecule, usually represented by the amino group (—NH2).


Figure 69-1 Amino acids. The 10 essential amino acids cannot be synthesized in sufficient quantities in the body; these essential amino acids must be obtained, already formed, from food.

Peptide Linkages and Peptide Chains

The amino acids of proteins are aggregated into long chains by means of peptide linkages. The chemical nature of this linkage is demonstrated by the following reaction:image

Note in this reaction that the nitrogen of the amino radical of one amino acid bonds with the carbon of the carboxyl radical of the other amino acid. A hydrogen ion is released from the amino radical, and a hydroxyl ion is released from the carboxyl radical; these two combine to form a molecule of water. After the peptide linkage has been formed, an amino radical and a carboxyl radical are still at opposite ends of the new, longer molecule. Each of these radicals is capable of combining with additional amino acids to form a peptide chain. Some complicated protein molecules have many thousand amino acids combined by peptide linkages, and even the smallest protein molecule usually has more than 20 amino acids combined by peptide linkages. The average is about 400 amino acids.

Other Linkages in Protein Molecules

Some protein molecules are composed of several peptide chains rather than a single chain, and these chains are bound to one another by other linkages, often by hydrogen bonding between the CO and NH radicals of the peptides, as follows:image

Many peptide chains are coiled or folded, and the successive coils or folds are held in a tight spiral or in other shapes by similar hydrogen bonding and other forces.

Transport and Storage of Amino Acids

Blood Amino Acids

The normal concentration of amino acids in the blood is between 35 and 65 mg/dl. This is an average of about 2 mg/dl for each of the 20 amino acids, although some are present in far greater amounts than others. Because the amino acids are relatively strong acids, they exist in the blood principally in the ionized state, resulting from the removal of one hydrogen atom from the NH2 radical. They actually account for 2 to 3 milliequivalents of the negative ions in the blood. The precise distribution of the different amino acids in the blood depends to some extent on the types of proteins eaten, but the concentrations of at least some individual amino acids are regulated by selective synthesis in the different cells.

Fate of Amino Acids Absorbed from the Gastrointestinal Tract

The products of protein digestion and absorption in the gastrointestinal tract are almost entirely amino acids; only rarely are polypeptides or whole protein molecules absorbed from the digestive tract into the blood. Soon after a meal, the amino acid concentration in a person’s blood rises, but the increase is usually only a few milligrams per deciliter, for two reasons: First, protein digestion and absorption are usually extended over 2 to 3 hours, which allows only small quantities of amino acids to be absorbed at a time. Second, after entering the blood, the excess amino acids are absorbed within 5 to 10 minutes by cells throughout the body, especially by the liver. Therefore, almost never do large concentrations of amino acids accumulate in the blood and tissue fluids. Nevertheless, the turnover rate of the amino acids is so rapid that many grams of proteins can be carried from one part of the body to another in the form of amino acids each hour.

Active Transport of Amino Acids into the Cells

The molecules of all the amino acids are much too large to diffuse readily through the pores of the cell membranes. Therefore, significant quantities of amino acids can move either inward or outward through the membranes only by facilitated transport or active transport using carrier mechanisms. The nature of some of the carrier mechanisms is still poorly understood, but a few are discussed in Chapter 4.

Renal Threshold for Amino Acids

In the kidneys, the different amino acids can be actively reabsorbed through the proximal tubular epithelium, which removes them from the glomerular filtrate and returns them to the blood if they should filter into the renal tubules through the glomerular membranes. However, as is true of other active transport mechanisms in the renal tubules, there is an upper limit to the rate at which each type of amino acid can be transported. For this reason, when the concentration of a particular type of amino acid becomes too high in the plasma and glomerular filtrate, the excess that cannot be actively reabsorbed is lost into the urine.

Storage of Amino Acids as Proteins in the Cells

Almost immediately after entry into tissue cells, amino acids combine with one another by peptide linkages, under the direction of the cell’s messenger RNA and ribosomal system, to form cellular proteins. Therefore, the concentration of free amino acids inside the cells usually remains low. Thus, storage of large quantities of free amino acids does not occur in the cells; instead, they are stored mainly in the form of actual proteins. But many of these intracellular proteins can be rapidly decomposed again into amino acids under the influence of intracellular lysosomal digestive enzymes; these amino acids can then be transported back out of the cell into the blood. Special exceptions to this reversal process are the proteins in the chromosomes of the nucleus and the structural proteins such as collagen and muscle contractile proteins; these proteins do not participate significantly in this reverse digestion and transport back out of the cells.

Some tissues of the body participate in the storage of amino acids to a greater extent than others. For instance, the liver, which is a large organ and has special systems for processing amino acids, can store large quantities of rapidly exchangeable proteins; this is also true to a lesser extent of the kidneys and the intestinal mucosa.

Release of Amino Acids from the Cells as a Means of Regulating Plasma Amino Acid Concentration

Whenever plasma amino acid concentrations fall below normal levels, the required amino acids are transported out of the cells to replenish their supply in the plasma. In this way, the plasma concentration of each type of amino acid is maintained at a reasonably constant value. Later, it is noted that some of the hormones secreted by the endocrine glands are able to alter the balance between tissue proteins and circulating amino acids. For instance, growth hormone and insulin increase the formation of tissue proteins, whereas adrenocortical glucocorticoid hormones increase the concentration of plasma amino acids.

Reversible Equilibrium Between the Proteins in Different Parts of the Body

Because cellular proteins in the liver (and, to a much less extent, in other tissues) can be synthesized rapidly from plasma amino acids, and because many of these proteins can be degraded and returned to the plasma almost as rapidly, there is constant interchange and equilibrium between the plasma amino acids and labile proteins in virtually all cells of the body. For instance, if any particular tissue requires proteins, it can synthesize new proteins from the amino acids of the blood; in turn, the blood amino acids are replenished by degradation of proteins from other cells of the body, especially from the liver cells. These effects are particularly noticeable in relation to protein synthesis in cancer cells. Cancer cells are often prolific users of amino acids; therefore, the proteins of the other cells can become markedly depleted.

Upper Limit for the Storage of Proteins

Each particular type of cell has an upper limit with regard to the amount of proteins it can store. After all the cells have reached their limits, the excess amino acids still in the circulation are degraded into other products and used for energy, as discussed subsequently, or they are converted to fat or glycogen and stored in these forms.

Functional Roles of the Plasma Proteins

The major types of protein present in the plasma are albumin, globulin, and fibrinogen.

A major function of albumin is to provide colloid osmotic pressure in the plasma, which prevents plasma loss from the capillaries, as discussed in Chapter 16.

The globulins perform a number of enzymatic functions in the plasma, but equally important, they are principally responsible for the body’s both natural and acquired immunity against invading organisms, discussed in Chapter 34.

Fibrinogen polymerizes into long fibrin threads during blood coagulation, thereby forming blood clots that help repair leaks in the circulatory system, discussed in Chapter 36.

Formation of the Plasma Proteins

Essentially all the albumin and fibrinogen of the plasma proteins, as well as 50 to 80 percent of the globulins, are formed in the liver. The remaining globulins are formed almost entirely in the lymphoid tissues. They are mainly the gamma globulins that constitute the antibodies used in the immune system.

The rate of plasma protein formation by the liver can be extremely high, as much as 30 g/day. Certain disease conditions cause rapid loss of plasma proteins; severe burns that denude large surface areas of the skin can cause the loss of several liters of plasma through the denuded areas each day. The rapid production of plasma proteins by the liver is valuable in preventing death in such states. Occasionally, a person with severe renal disease loses as much as 20 grams of plasma protein in the urine each day for months, and it is continually replaced mainly by liver production of the required proteins.

In cirrhosis of the liver, large amounts of fibrous tissue develop among the liver parenchymal cells, causing a reduction in their ability to synthesize plasma proteins. As discussed in Chapter 25, this leads to decreased plasma colloid osmotic pressure, which causes generalized edema.

Plasma Proteins as a Source of Amino Acids for the Tissues

When the tissues become depleted of proteins, the plasma proteins can act as a source of rapid replacement. Indeed, whole plasma proteins can be imbibed in toto by tissue macrophages through the process of pinocytosis; once in these cells, they are split into amino acids that are transported back into the blood and used throughout the body to build cellular proteins wherever needed. In this way, the plasma proteins function as a labile protein storage medium and represent a readily available source of amino acids whenever a particular tissue requires them.

Reversible Equilibrium Between the Plasma Proteins and the Tissue Proteins

There is a constant state of equilibrium, as shown in Figure 69-2, among the plasma proteins, the amino acids of the plasma, and the tissue proteins. It has been estimated from radioactive tracer studies that normally about 400 grams of body protein are synthesized and degraded each day as part of the continual state of flux of amino acids. This demonstrates the general principle of reversible exchange of amino acids among the different proteins of the body. Even during starvation or severe debilitating diseases, the ratio of total tissue proteins to total plasma proteins in the body remains relatively constant at about 33:1.


Figure 69-2 Reversible equilibrium among the tissue proteins, plasma proteins, and plasma amino acids.

Because of this reversible equilibrium between plasma proteins and the other proteins of the body, one of the most effective therapies for severe, acute whole-body protein deficiency is intravenous transfusion of plasma protein. Within a few days, or sometimes within hours, the amino acids of the administered protein are distributed throughout the cells of the body to form new proteins as needed.

Essential and Nonessential Amino Acids

Ten of the amino acids normally present in animal proteins can be synthesized in the cells, whereas the other 10 either cannot be synthesized or are synthesized in quantities too small to supply the body’s needs. This second group of amino acids that cannot be synthesized is called the essential amino acids. Use of the word “essential” does not mean that the other 10 “nonessential” amino acids are not required for the formation of proteins, but only that the others are not essential in the diet because they can be synthesized in the body.

Synthesis of the nonessential amino acids depends mainly on the formation of appropriate α-keto acids, which are the precursors of the respective amino acids. For instance, pyruvic acid, which is formed in large quantities during the glycolytic breakdown of glucose, is the keto acid precursor of the amino acid alanine. Then, by the process of transamination, an amino radical is transferred to the α-keto acid, and the keto oxygen is transferred to the donor of the amino radical. This reaction is shown in Figure 69-3. Note in this figure that the amino radical is transferred to the pyruvic acid from another chemical that is closely allied to the amino acids—glutamine. Glutamine is present in the tissues in large quantities, and one of its principal functions is to serve as an amino radical storehouse. In addition, amino radicals can be transferred from asparagine, glutamic acid, and aspartic acid.


Figure 69-3 Synthesis of alanine from pyruvic acid by transamination.

Transamination is promoted by several enzymes, among which are the aminotransferases, which are derivatives of pyridoxine, one of the B vitamins (B6). Without this vitamin, the amino acids are synthesized only poorly and protein formation cannot proceed normally.

Use of Proteins for Energy

Once the cells are filled to their limits with stored protein, any additional amino acids in the body fluids are degraded and used for energy or are stored mainly as fat or secondarily as glycogen. This degradation occurs almost entirely in the liver, and it begins with deamination, which is explained in the following section.


Deamination means removal of the amino groups from the amino acids. This occurs mainly by transamination, which means transfer of the amino group to some acceptor substance, which is the reverse of the transamination explained earlier in relation to the synthesis of amino acids.

The greatest amount of deamination occurs by the following transamination schema:image

Note from this schema that the amino group from the amino acid is transferred to α-ketoglutaric acid, which then becomes glutamic acid. The glutamic acid can then transfer the amino group to still other substances or release it in the form of ammonia (NH3). In the process of losing the amino group, the glutamic acid once again becomes α-ketoglutaric acid, so the cycle can be repeated again and again. To initiate this process, the excess amino acids in the cells, especially in the liver, induce the activation of large quantities of aminotransferases, the enzymes responsible for initiating most deamination.

Urea Formation by the Liver

The ammonia released during deamination of amino acids is removed from the blood almost entirely by conversion into urea; two molecules of ammonia and one molecule of carbon dioxide combine in accordance with the following net reaction:


Essentially all urea formed in the human body is synthesized in the liver. In the absence of the liver or in serious liver disease, ammonia accumulates in the blood. This is extremely toxic, especially to the brain, often leading to a state called hepatic coma.

The stages in the formation of urea are essentially the following:image

After its formation, the urea diffuses from the liver cells into the body fluids and is excreted by the kidneys.

Oxidation of Deaminated Amino Acids

Once amino acids have been deaminated, the resulting keto acids can, in most instances, be oxidized to release energy for metabolic purposes. This usually involves two successive processes: (1) The keto acid is changed into an appropriate chemical substance that can enter the citric acid cycle, and (2) this substance is degraded by the cycle and used for energy in the same manner that acetyl coenzyme A (acetyl-CoA) derived from carbohydrate and lipid metabolism is used, as explained in Chapters 67 and 68. In general, the amount of adenosine triphosphate (ATP) formed for each gram of protein that is oxidized is slightly less than that formed for each gram of glucose oxidized.

Gluconeogenesis and Ketogenesis

Certain deaminated amino acids are similar to the substrates normally used by the cells, mainly the liver cells, to synthesize glucose or fatty acids. For instance, deaminated alanine is pyruvic acid. This can be converted into either glucose or glycogen. Alternatively, it can be converted into acetyl-CoA, which can then be polymerized into fatty acids. Also, two molecules of acetyl-CoA can condense to form acetoacetic acid, which is one of the ketone bodies, as explained in Chapter 68.

The conversion of amino acids into glucose or glycogen is called gluconeogenesis, and the conversion of amino acids into keto acids or fatty acids is called ketogenesis. Of the 20 deaminated amino acids, 18 have chemical structures that allow them to be converted into glucose, and 19 of them can be converted into fatty acids.

Obligatory Degradation of Proteins

When a person eats no proteins, a certain proportion of body proteins is degraded into amino acids and then deaminated and oxidized. This involves 20 to 30 grams of protein each day, which is called the obligatory loss of proteins. Therefore, to prevent net loss of protein from the body, one must ingest a minimum of 20 to 30 grams of protein each day; to be on the safe side, a minimum of 60 to 75 grams is usually recommended.

The ratios of the different amino acids in the dietary protein must be about the same as the ratios in the body tissues if the entire dietary protein is to be fully usable to form new proteins in the tissues. If one particular type of essential amino acid is low in concentration, the others become unusable because cells synthesize either whole proteins or none at all, as explained in Chapter 3 in relation to protein synthesis. The unusable amino acids are deaminated and oxidized. A protein that has a ratio of amino acids different from that of the average body protein is called a partial protein or incomplete protein, and such a protein is less valuable for nutrition than is a complete protein.

Effect of Starvation on Protein Degradation

Except for the 20 to 30 grams of obligatory protein degradation each day, the body uses almost entirely carbohydrates or fats for energy, as long as they are available. However, after several weeks of starvation, when the quantities of stored carbohydrates and fats begin to run out, the amino acids of the blood are rapidly deaminated and oxidized for energy. From this point on, the proteins of the tissues degrade rapidly—as much as 125 grams daily—and, as a result, cellular functions deteriorate precipitously. Because carbohydrate and fat utilization for energy normally occurs in preference to protein utilization, carbohydrates and fats are called protein sparers.

Hormonal Regulation of Protein Metabolism

Growth Hormone Increases the Synthesis of Cellular Proteins

Growth hormone causes the tissue proteins to increase. The precise mechanism by which this occurs is not known, but it is believed to result mainly from increased transport of amino acids through the cell membranes, acceleration of the DNA and RNA transcription and translation processes for protein synthesis, and decreased oxidation of tissue proteins.

Insulin Is Necessary for Protein Synthesis

Total lack of insulin reduces protein synthesis to almost zero. Insulin accelerates the transport of some amino acids into cells, which could be the stimulus to protein synthesis. Also, insulin reduces protein degradation and increases the availability of glucose to the cells, so the need for amino acids for energy is correspondingly reduced.

Glucocorticoids Increase Breakdown of Most Tissue Proteins

The glucocorticoids secreted by the adrenal cortex decrease the quantity of protein in most tissues while increasing the amino acid concentration in the plasma, as well as increasing both liver proteins and plasma proteins. It is believed that the glucocorticoids act by increasing the rate of breakdown of extrahepatic proteins, thereby making increased quantities of amino acids available in the body fluids. This allows the liver to synthesize increased quantities of hepatic cellular proteins and plasma proteins.

Testosterone Increases Protein Deposition in Tissues

Testosterone, the male sex hormone, causes increased deposition of protein in tissues throughout the body, especially the contractile proteins of the muscles (30 to 50 percent increase). The mechanism of this effect is unknown, but it is definitely different from the effect of growth hormone, in the following way: Growth hormone causes tissues to continue growing almost indefinitely, whereas testosterone causes the muscles and, to a much lesser extent, some other protein tissues to enlarge for only several months. Once the muscles and other protein tissues have reached a maximum, despite continued administration of testosterone, further protein deposition ceases.


Estrogen, the principal female sex hormone, also causes some deposition of protein, but its effect is relatively insignificant in comparison with that of testosterone.


Thyroxine increases the rate of metabolism of all cells and, as a result, indirectly affects protein metabolism. If insufficient carbohydrates and fats are available for energy, thyroxine causes rapid degradation of proteins and uses them for energy. Conversely, if adequate quantities of carbohydrates and fats are available and excess amino acids are also available in the extracellular fluid, thyroxine can actually increase the rate of protein synthesis. In growing animals or human beings, deficiency of thyroxine causes growth to be greatly inhibited because of lack of protein synthesis. In essence, it is believed that thyroxine has little specific effect on protein metabolism but does have an important general effect by increasing the rates of both normal anabolic and normal catabolic protein reactions.


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