Protein Metabolism pdf - Metabolism and Temperature Regulation

The chemical nature of this linkage is

peptide linkages.

In proteins, the amino acids are aggregated into

attached to the molecule, usually represented by the amino group (—NH

common: each amino acid has an acidic group (—COOH) and a nitrogen atom

las of these 20 amino acids, demonstrating that they all have two features in

the body proteins in significant quantities. Figure 69–1 shows the chemical formu-

The principal constituents of proteins are amino acids, 20 of which are present in

Basic Properties

biochemistry. For this reason, the current discussion is confined to a few specific

The basic chemical properties that explain proteins’

lar functions throughout the body.

muscle that cause muscle contraction, and many other

teins, proteins that transport oxygen, proteins of the

These include structural proteins, enzymes, nucleopro-

About three quarters of the body solids are proteins.

852

Protein Metabolism

types that perform specific intracellular and extracellu-

diverse functions are so extensive that they
constitute a major portion of the entire discipline of

aspects of protein metabolism that are important as background for other discus-
sions in this text.

Amino Acids

Peptide Linkages and Peptide Chains.

long chains by means of
demonstrated by the following reaction:

COOH

+ R'

H NH

COOH

peptide chains rather than a single chain, and these chains are bound to one another

peptide linkages. The average is about 400 amino acids.

molecules have many thousand amino acids combined by peptide linkages, and even

peptide chain.

site ends of the new, longer molecule. Each of these radicals is capable of combin-

linkage has been formed, an amino radical and a carboxyl radical are still at oppo-

boxyl radical; these two combine to form a molecule of water. After the peptide

ion is released from the amino radical, and a hydroxyl ion is released from the car-

bonds with the carbon of the carboxyl radical of the other amino acid. A hydrogen

Note in this reaction that the nitrogen of the amino radical of one amino acid

ing with additional amino acids to form a

Some complicated protein

the smallest protein molecule usually has more than 20 amino acids combined by

Other Linkages in Protein Molecules.

Some protein molecules are composed of several

Chapter 69

Protein Metabolism

853

VALINE

PHENYLALANINE

LEUCINE

TRYPTOPHAN

Glycine

Proline

NH H

COOH

Alanine

Glutamine

Asparagine

Serine

Cysteine

Aspartic Acid

Glutamic Acid

HISTIDINE

ISOLEUCINE

Tyrosine

METHIONINE

THREONINE

AMINO ACIDS

LYSINE

ESSENTIAL AMINO ACIDS

ARGININE

be obtained, already formed, from food.

amino acids cannot be synthesized in sufficient quantities in the body; these essential amino acids must

Figure 69–1

Amino acids. The 10 essential

nisms is still poorly understood, but a few are discussed

mechanisms. The nature of some of the carrier mecha-

fore, significant quantities of amino acids can move

readily through the pores of the cell membranes. There-

The molecules

Active Transport of Amino Acids into the Cells.

form of amino acids each hour.

and tissue fluids. Nevertheless, the turnover rate of the

especially by the liver. Therefore, almost never do large

within 5 to 10 minutes by cells throughout the body,

entering the blood, the excess amino acids are absorbed

amino acids to be absorbed at a time. Second, after

over 2 to 3 hours, which allows only small quantities of

few milligrams per deciliter, for two reasons: First,

person’s blood rises, but the increase is usually only a

diately after a meal, the amino acid concentration in a

absorbed from the digestive tract into the blood. Imme-

The products of protein digestion and absorption in the

Fate of Amino Acids Absorbed from the Gastrointestinal Tract.

ent cells.

to some extent on the types of proteins eaten, but

of the negative ions in the blood. The precise distribu-

radical. They actually account for 2 to 3 milliequivalents

in the blood principally in the ionized state, resulting

the amino acids are relatively strong acids, they exist

are present in far greater amounts than others. Because

2 mg/dl for each of the 20 amino acids, although some

is between 35 and 65 mg/dl. This is an average of about

The normal concentration of amino acids in the blood

Transport and Storage

shapes by similar hydrogen bonding and other forces.

Many peptide chains are coiled or folded, and the suc-

the CO and NH radicals of the peptides, as follows:

by other linkages, often by

Metabolism and Temperature Regulation

854

Unit XIII

hydrogen bonding between

cessive coils or folds are held in a tight spiral or in other

of Amino Acids

Blood Amino Acids

from the removal of one hydrogen atom from the NH

tion of the different amino acids in the blood depends

the concentrations of at least some individual amino
acids are regulated by selective synthesis in the differ-

gastrointestinal tract are almost entirely amino acids;
only rarely are polypeptides or whole protein molecules

protein digestion and absorption are usually extended

concentrations of amino acids accumulate in the blood

amino acids is so rapid that many grams of proteins can
be carried from one part of the body to another in the

of all the amino acids are much too large to diffuse

either inward or outward through the membranes only
by facilitated transport or active transport using carrier

in Chapter 4.

instance, if any particular tissue requires proteins, it can

labile proteins in virtually all cells of the body. For

plasma almost as rapidly, there is constant interchange

rapidly from plasma amino acids, and because many of

a much less extent, in other tissues) can be synthesized

Because cellular proteins in the liver (and, to

the Body.

mones increase the concentration of plasma amino acids.

proteins, whereas adrenocortical glucocorticoid hor-

teins and circulating amino acids. For instance, growth

tained at a reasonably constant value. Later, it is noted

replenish their supply in the plasma. In this way, the

acid concentrations fall below normal levels, the

Whenever plasma amino

quantities of rapidly exchangeable proteins; this is also

systems for processing amino acids, can store large

instance, the liver, which is a large organ and has special

of amino acids to a greater extent than others. For

transport back out of the cells.

and muscle contractile proteins; these proteins do not

cell into the blood. Special exceptions to this reversal

of intracellular lysosomal digestive enzymes; these

they are stored mainly in the form of actual proteins.

of free amino acids does not occur in the cells; instead,

usually remains low. Thus, storage of large quantities

ribosomal system, to form cellular proteins. Therefore,

under the direction of the cell’s messenger RNA and

acids combine with one another by peptide linkages,

Almost immediately after entry into tissue cells, amino

in the Cells

Storage of Amino Acids as Proteins

reabsorbed is lost into the urine.

glomerular filtrate, the excess that cannot be actively

reason, when the concentration of a particular type

each type of amino acid can be transported. For this

renal tubules, there is an upper limit to the rate at which

tubules through the glomerular membranes. However,

through the proximal tubular epithelium, which

In the kidneys, the

Renal Threshold for Amino Acids.

different amino acids can be actively reabsorbed

removes them from the glomerular filtrate and returns
them to the blood if they should filter into the renal

as is true of other active transport mechanisms in the

of amino acid becomes too high in the plasma and

the concentration of free amino acids inside the cells

But many of these intracellular proteins can be rapidly
decomposed again into amino acids under the influence

amino acids can then be transported back out of the

process are the proteins in the chromosomes of the
nucleus and the structural proteins such as collagen

participate significantly in this reverse digestion and

Some tissues of the body participate in the storage

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.

required amino acids are transported out of the cells to

plasma concentration of each type of amino acid is main-

that some of the hormones secreted by the endocrine
glands are able to alter the balance between tissue pro-

hormone and insulin increase the formation of tissue

Reversible Equilibrium Between the Proteins in Different Parts of

these proteins can be degraded and returned to the

and equilibrium between the plasma amino acids and

synthesize new proteins from the amino acids of the

-keto acids,

because they can be synthesized in the body.

proteins, but only that the others are

tial” amino acids are not required for the formation of

“essential” does not mean that the other 10 “nonessen-

essential amino acids.

quantities too small to supply the body’s needs. This

teins can be synthesized in the cells, whereas the other

Ten of the amino acids normally present in animal pro-

hours, the amino acids of the administered protein are

plasma protein. Within a few days, or sometimes within

body protein deficiency is intravenous transfusion of

of the most effective therapies for severe, acute whole-

plasma proteins and the other proteins of the body, one

starvation or severe debilitating diseases, the ratio of

among the different proteins of the body. Even during

state of flux of amino acids. This demonstrates the

amino acids of the plasma, and the tissue proteins. It has

as shown in Figure 69–2, among the plasma proteins, the

There is a constant state of equilibrium,

Tissue Proteins.

needed. In this way, the plasma proteins function as a

pinocytosis; once in these cells, they are split into amino

ment. Indeed, whole plasma proteins can be imbibed in

When the tissues become depleted of proteins, the

Plasma Proteins as a Source of Amino Acids for the Tissues.

plasma colloid osmotic pressure, which causes general-

As discussed in Chapter 25, this leads to decreased

reduction in their ability to synthesize plasma proteins.

develop among the liver parenchymal cells, causing a

cirrhosis of the liver,

proteins.

the urine each day for months, and it is continually

such states. Occasionally, a person with severe renal

denuded areas each day. The rapid production of plasma

conditions cause rapid loss of plasma proteins; severe

be extremely high, as much as 30 g/day. Certain disease

The rate of plasma protein formation by the liver can

entirely in the lymphoid tissues. They are mainly the

liver. The remainder of the globulins are formed almost

as 50 to 80 per cent of the globulins, are formed in the

albumin and fibrinogen of the plasma proteins, as well

that help repair leaks in the circulatory system, dis-

during blood coagulation, thereby

against invading organisms, dis-

cipally responsible for the body’s both natural and

in the plasma, but equally important, they are prin-

The

loss from the capillaries, as discussed in Chapter 16.

in the plasma, which prevents plasma

albumin, globulin,

The major types of protein present in the plasma are

Plasma Proteins

or glycogen and stored in these forms.

as discussed subsequently, or they are converted to fat

are degraded into other products and used for energy,

their limits, the excess amino acids still in the circulation

proteins it can store. After all the cells have reached

therefore, the proteins of the other cells can become

cells. Cancer cells are often prolific users of amino acids;

especially from the liver cells. These effects are particu-

degradation of proteins from other cells of the body,

blood; in turn, the blood amino acids are replenished by

Chapter 69

Protein Metabolism

855

larly noticeable in relation to protein synthesis in cancer

markedly depleted.

Upper Limit for the Storage of Proteins.

Each particular type

of cell has an upper limit with regard to the amount of

Functional Roles of the

and fibrinogen.

A major function of albumin is to provide colloid

osmotic pressure

globulins perform a number of enzymatic func-

tions

acquired immunity
cussed in Chapter 34.

Fibrinogen polymerizes into long fibrin threads

forming blood clots

cussed in Chapter 36.

Formation of the Plasma Proteins.

Essentially all the

gamma globulins that constitute the antibodies used in
the immune system.

burns that denude large surface areas of the skin can
cause the loss of several liters of plasma through the

proteins by the liver is valuable in preventing death in

disease loses as much as 20 grams of plasma protein in

replaced mainly by liver production of the required

large amounts of fibrous tissue

ized edema.

plasma proteins can act as a source of rapid replace-

toto by tissue macrophages through the process of

acids that are transported back into the blood and used

throughout the body to build cellular proteins wherever

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

been estimated from radioactive tracer studies that
normally about 400 grams of body protein are synthe-
sized and degraded each day as part of the continual

general principle of reversible exchange of amino acids

total tissue proteins to total plasma proteins in the body
remains relatively constant at about 33:1.

Because of this reversible equilibrium between

distributed throughout the cells of the body to form new
proteins where they are needed.

Essential and Nonessential
Amino Acids

10 either cannot be synthesized or are synthesized in

second group of amino acids that cannot be synthesized
is called the

Use of the word

not essential in the

diet

Synthesis of the nonessential amino acids depends

mainly on the formation of appropriate

Amino acids

Blood

Tissue cells

Liver cells

Tissue cells

Liver cells

Proteins

Amino acids

Proteins

Amino acids

Amino
acids

Proteins

Plasma proteins

Imbibed plasma protein

Reticuloendothelial cell

Amino acids

Blood

Reversible equilibrium among the tissue proteins, plasma pro-

Figure 69–2

teins, and plasma amino acids.

cycle, and (2) this substance is degraded by the cycle and

processes: (1) the keto acid is changed into an appro-

bolic purposes. This usually involves two successive

most instances, be oxidized to release energy for meta-

have been deaminated, the resulting keto acids can, in

into the body fluids and is excreted by the kidneys.

After its formation, the urea diffuses from the liver cells

The stages in the formation of urea are essentially the

blood. This is extremely toxic, especially to the brain,

serious liver disease, ammonia accumulates in the

thesized in the liver. In the absence of the liver or in

blood almost entirely by conversion into urea; two mol-

The ammonia released

Urea Formation by the Liver.

ferases,

excess amino acids in the cells, especially in the liver,

repeated again and again. To initiate this process, the

-ketoglutaric acid, so that the cycle can be

of losing the amino group, the glutamic acid once again

). In the process

then becomes glutamic acid. The glutamic acid can then

-ketoglutaric acid, which

The greatest amount of deamination occurs by the

synthesis of amino acids.

group to some acceptor substance, which is the reverse

transamination, which means transfer of the amino

groups from the amino acids. This occurs mainly by

almost entirely in the liver, and it begins with

or secondarily as glycogen. This degradation occurs

protein, any additional amino acids in the body fluids are

and protein formation cannot proceed normally.

this vitamin, the amino acids are synthesized only poorly,

). Without

atives of pyridoxine, one of the B vitamins (B

aminotransferases,

Transamination is promoted by several enzymes,

asparagine, glutamic

serve as an amino radical storehouse. In addition, amino

large quantities, and one of its principal functions is to

glutamine.

acids,

This reaction is shown in Figure 69–3. Note in this figure

-keto acid, and the keto

Then, by the process of

alanine.

quantities during the glycolytic breakdown of glucose,

pyruvic acid,

For instance,

which are the precursors of the respective amino acids.

Metabolism and Temperature Regulation

856

Unit XIII

which is formed in large

is the keto acid precursor of the amino acid

transamination, an amino

radical is transferred to the

oxygen is transferred to the donor of the amino radical.

that the amino radical is transferred to the pyruvic acid
from another chemical that is closely allied to the amino

Glutamine is present in the tissues in

radicals can be transferred from
acid, and aspartic acid.

among which are the

which are deriv-

Use of Proteins for Energy

Once the cells are filled to their limits with stored

degraded and used for energy or are stored mainly as fat

deamina-

tion, which is explained in the following section.

Deamination.

Deamination means removal of the amino

of the transamination explained earlier in relation to the

following transamination schema:

Note from this schema that the amino group from the

amino acid is transferred to

transfer the amino group to still other substances or
release it in the form of ammonia (NH

becomes

induce the activation of large quantities of aminotrans-

the enzymes responsible for initiating most

deamination.

during deamination of amino acids is removed from the

ecules of ammonia and one molecule of carbon dioxide
combine in accordance with the following net reaction:

2 NH

+ CO

Æ H

N—C—NH

+ H

Essentially all urea formed in the human body is syn-

often leading to a state called hepatic coma.

following:

Oxidation of Deaminated Amino Acids.

Once amino acids

priate chemical substance that can enter the citric acid

(Arginase)

Arginine

Citrulline

Urea

Ornithine

+ CO

+ NH

-H

+ H

-H

-Ketoglutamic acid)

(Alanine)

(Glutamine)

(Pyruvic acid)

(

Transaminase

COOH

Synthesis of alanine from pyruvic

Figure 69–3

acid by transamination.

Amino acid

a-Ketoglutaric acid +

Glutamic acid

a-Keto acid

+ NAD

+ H

NADH

+ H

+ NH

reactions.

essence, it is believed that thyroxine has little specific

inhibited because of lack of protein synthesis. In

deficiency of thyroxine causes growth to be greatly

protein synthesis. In growing animals or human beings,

cellular fluid, thyroxine can actually increase the rate of

proteins and uses them for energy. Conversely, if ade-

able for energy, thyroxine causes rapid degradation of

olism. If insufficient carbohydrates and fats are avail-

all cells and, as a result, indirectly affects protein metab-

Thyroxine increases the rate of metabolism of

testosterone.

also causes some deposition of protein, but its effect

Estrogen, the principal female sex hormone,

tion ceases.

administration of testosterone, further protein deposi-

tissues have reached a maximum, despite continued

several months. Once the muscles and other protein

extent, some other protein tissues to enlarge for only

testosterone causes the muscles and, to a much lesser

tissues to continue growing almost indefinitely, whereas

hormone, in the following way: Growth hormone causes

increase). The mechanism of this effect is unknown, but

tion of protein in tissues throughout the body, especially

terone, the male sex hormone, causes increased deposi-

Testos-

Testosterone Increases Protein Deposition in Tissues.

cellular proteins and plasma proteins.

acids available in the body fluids. This supposedly allows

teins, thereby making increased quantities of amino

teins.

The glucocorticoids secreted by the adrenal cortex

Glucocorticoids Increase Breakdown of Most Tissue Proteins.

glucose to the cells, so that the need for amino acids for

synthesis. Also, insulin increases the availability of

acids into cells, which could be the stimulus to protein

mechanism by which this occurs is also unknown, but

insulin reduces protein synthesis to almost zero. The

Total lack of

Insulin Is Necessary for Protein Synthesis.

translation processes for protein synthesis.

acceleration of the DNA and RNA transcription and

known, but it is believed to result mainly from increased

The precise mechanism by which this occurs is not

Growth hormone causes the tissue proteins to increase.

of Protein Metabolism

Hormonal Regulation

sparers.

utilization, carbohydrates and fats are called

precipitously. Because carbohydrate and fat utilization

daily—and, as a result, cellular functions deteriorate

oxidized for energy. From this point on, the proteins

of stored carbohydrates and fats begin to run out, the

after several weeks of starvation, when the quantities

for energy, as long as they are available. However,

to 30 grams of obligatory protein degradation each day,

Effect of Starvation on Protein Degradation.

acids are deaminated and oxidized. A protein that has

in relation to protein synthesis. The unusable amino

whole proteins or none at all, as explained in Chapter 3

of essential amino acid is low in concentration, the

to form new proteins in the tissues. If one particular type

The ratios of the different amino acids in the dietary

safe side, a minimum of 60 to 75 grams is usually

of 20 to 30 grams of protein each day; to be on the

protein from the body, one must ingest a minimum

of proteins. Therefore, to prevent net loss of

of protein each day, which is called the

deaminated and oxidized. This involves 20 to 30 grams

When a person eats no proteins, a certain proportion of

Obligatory Degradation of Proteins

acids.

glucose, and 19 of them can be converted into fatty

Of the 20 deaminated amino acids, 18 have

genesis.

gluconeogenesis,

The conversion of amino acids into glucose or glyco-

bodies, as explained in Chapter 68.

to form acetoacetic acid, which is one of the ketone

acids. Also, two molecules of acetyl-CoA can condense

acetyl-CoA, which can then be polymerized into fatty

or glycogen. Alternatively, it can be converted into

pyruvic acid. This can be converted into either glucose

or fatty acids. For instance, deaminated alanine is

by the cells, mainly the liver cells, to synthesize glucose

phate (ATP) formed for each gram of protein that is

and 68. In general, the amount of adenosine triphos-

lipid metabolism is used, as explained in Chapters 67

zyme A (acetyl-CoA) derived from carbohydrate and

Chapter 69

Protein Metabolism

857

used for energy in the same manner that acetyl coen-

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

gen is called

and the conversion of

amino acids into keto acids or fatty acids is called keto-

chemical structures that allow them to be converted into

body proteins is degraded into amino acids and then

obligatory

loss

recommended.

protein must be about the same as the ratios in the body
tissues if the entire dietary protein is to be fully usable

others become unusable because cells synthesize either

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.

Except for the 20

the body uses almost entirely carbohydrates or fats

amino acids of the blood are rapidly deaminated and

of the tissues degrade rapidly—as much as 125 grams

for energy normally occurs in preference to protein

protein

Growth Hormone Increases the Synthesis of Cellular Proteins.

transport of amino acids through the cell membranes or

insulin does accelerate the transport of some amino

energy is correspondingly reduced.

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 pro-

It is believed that the glucocorticoids act by

increasing the rate of breakdown of extrahepatic pro-

the liver to synthesize increased quantities of hepatic

the contractile proteins of the muscles (30 to 50 per cent

it is definitely different from the effect of growth

Estrogen.

is relatively insignificant in comparison with that of

Thyroxine.

quate quantities of carbohydrates and fats are available
and excess amino acids are also available in the extra-

effect on protein metabolism but does have an
important general effect by increasing the rates of
both normal anabolic and normal catabolic protein

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olism of amino acids: its role in interorgan amino acid

van de Poll MC, Soeters PB, Deutz NE, et al: Renal metab-

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Tessari P: Protein metabolism in liver cirrhosis: from albumin

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Prod’homme M, Rieu I, Balage M, et al: Insulin and amino

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Pencharz PB, Ball RO: Amino acid needs for early growth

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Moriwaki H, Miwa Y, Tajika M, et al: Branched-chain amino

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Meijer AJ: Amino acids as regulators and components of

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Mann GE, Yudilevich DL, Sobrevia L: Regulation of amino

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Metabolism and Temperature Regulation

858

Unit XIII

References

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